Intravaginal devices for controlled delivery of lubricants

ABSTRACT

The present technology provides intravaginal devices designed to deliver lubricants to the vagina for a sustained period of time. The intravaginal devices include a first segment comprising an outer surface and a lumen containing a lubricant, wherein the first segment is configured to deliver the contents of the lumen to the outer surface, and the first segment comprises a polymer selected from the group consisting of a hydrophilic, semi-permeable elastomer and a hydrophobic elastomer. The lubricant may be an aqueous lubricant. The present technology further provides an intravaginal device including a solid first segment that includes a hydrophilic semi-permeable elastomer, an outer surface and an aqueous lubricant, wherein the first segment is configured to deliver the aqueous lubricant to the outer surface.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/709,138 filed May 11, 2015, which is a continuation of U.S.application Ser. No. 13/884,936 filed Nov. 12, 2013, which is a U.S.national phase application of International Application Serial No.PCT/US2011/060389, filed on Nov. 11, 2011, which claims priority to U.S.Provisional Application No. 61/413,238 filed Nov. 12, 2010, U.S.Provisional Application No. 61/516,582 filed Apr. 5, 2011, and U.S.Provisional Application No. 61/542,552 filed Oct. 3, 2011, the contentsof each of which are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY

The present technology relates to devices and methods for intravaginaldelivery of lubricants, including, e.g., aqueous and non-aqueous,including hypo-osmotic, iso-osmotic, and hyper-osmotic lubricants, waterand gels.

BACKGROUND

Vaginal dryness is a common problem for many women. Although it istraditionally considered to be a condition that affects postmenopausalwomen, it can occur during the premenopausal and perimenopausal years,as well as throughout their lifetime. Current therapies for increasingvaginal moisture include lubricating creams or jellies, topical estrogencreams, and HRT (hormone replacement therapy). Lubricating jellies areoften messy to use and provide short-lived and temporary relief. Topicalestrogen creams, if used on a regular basis, may be absorbed into thesystemic circulation. This can cause endometrial stimulation and canlead to endometrial hyperplasia and carcinoma. HRT is widely used andeffective at relieving symptoms of, e.g., vaginal atrophy and hencevaginal dryness. However, recent studies indicate that HRT can increaserisk of heart attacks, stroke, blood clots, and breast cancer in somewomen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an illustrative embodiment of an intravaginal device (IVD)of the present technology that is an intravaginal ring (IVR) having asingle segment and including multiple slits. The IVR is constructed ofhydrophobic elastomeric tubing, which contains a vaginal lubricant inthe lumen. The ends of the tubing are joined by a plug, which fitswithin each end of the tubing.

FIG. 2 A-F shows six illustrative embodiments of IVRs of the presenttechnology. FIG. 2A shows an IVR constructed from a semi-permeableelastomer 10 to allow for the diffusion of lubricant from the lumen 30,through the hydrophilic elastomer, to the outer surface of the ring. TheIVR is formed from a single segment of hydrophilic elastomeric tubingjoined by a plastic weld 40. FIG. 2B shows a dual segment IVR. Onesegment of this IVR is constructed from a semi-permeable elastomer 10having a lumen 30 filled with lubricant. A second segment 80 isconstructed out of a hydrophobic elastomer with pores or holes 60 thatextend from the surface of the segment to the lumen 70, which is filledwith a lubricant as well (e.g., a gel). The two segments are joined atthe ends and the lumens are separated by polymer plugs 50. FIG. 2C showsan IVR similar to the one shown in FIG. 2A, but including a pod that maycontain additional lubricant (the same or different from that in lumen30) or other additives for regulating the vaginal environment, e.g.,probiotics. FIGS. 2D, 2E, and 2F illustrate supported variations of thevarious IVRs. In each of the IVRs of FIGS. 2D, 2E, and 2F, supportsprings are incorporated into the walls of, respectively, the singlesegment IVR of FIG. 2A, the dual segment IVR of FIG. 2B and thepod-containing IVR of FIG. 2C.

FIG. 3 shows an illustrative embodiment of the present technology thatis a dual segment IVR in which each segment includes a lumen. Onesegment is constructed of semi-permeable hydrophilic elastomer andcontaining a lubricant, e.g., water. The second segment is alsoconstructed of a hydrophilic elastomer and includes multiple slitsextending from the lumen to the surface of the segment, allowing adifferent lubricant, e.g. gel, to be released. The ends of each segmentare joined by plugs, which separate the contents of the two lumens.

FIG. 4 shows an illustrative embodiment of the present technology thatis a matrix IVR. The IVR is constructed of a single solid rod ofswellable hydrophilic elastomer, by, e.g., injection molding. The matrixIVR may be “loaded” with lubricant simply by soaking in the desiredlubricant for a suitable length of time.

FIG. 5 shows an illustrative embodiment of the present technology thatis a dual segment IVR. One segment is constructed out of a solid lengthof swellable hydrophilic elastomer. The other segment is also made of ahydrophilic elastomer, but includes a lumen and is supported internallyby a spring to provide extra mechanical stiffness similar to the matrixsegment.

FIG. 6 illustrative embodiment of the present technology that is amatrix IVR with a pod attached. The ring portion of the IVR isconstructed of a swellable hydrophilic elastomer. The pod may containadditional lubricant or other additives such as probiotics.

FIG. 7 illustrative embodiment of the present technology that is amatrix IVR with a lubricant containing ovule attached. The ovulecontains glycerol encapsulated in gelatin.

FIG. 8 illustrative embodiment of the present technology that is a dualsegment IVR with a pod attached. The pod-containing segment isconstructed from a solid hydrophilic elastomer. The pod may containadditional lubricant or other additives such as, e.g., probiotics. Theother segment is also made of a hydrophilic elastomer but includes alumen and is supported internally by a spring to provide extramechanical stiffness similar to the matrix segment.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. The illustrativeembodiments described in the detailed description, drawings, and claimsare not meant to be limiting. Other embodiments may be utilized, andother changes may be made, without departing from the spirit or scope ofthe subject matter presented here.

The present technology provides devices and methods for intravaginaldelivery of lubricants such as aqueous lubricants. Lubricants of thepresent technology include only those lubricants that are suitable foruse on vaginal tissues. By “aqueous lubricant” is meant water or anywater-based solution, emulsion, suspension, gel or foam that can providelubrication and moisture to the vaginal tissues. In particular, use ofintravaginal devices of the present technology directly relieve thesymptoms of vaginal atrophy, dryness, irritation, pain and discomfort.The aqueous lubricants released by the present devices can soothe andrevitalize or restore dry tissues within the vaginal mucosa. Thelubricants may also be formulated to maintain appropriate pH andphysiology and promote a normal vaginal environment. Thus, the presentdevices are non-irritating, safe, easy to use, and typically, hormonefree. They may be designed for use over several hours, a single day orcontinuously for up to 30 days.

In accordance with one aspect, the present technology providesintravaginal devices that include a first segment that includes an outersurface and a lumen containing a lubricant, e.g., an aqueous lubricant,moisturizing or wetting agent. The first segment is configured todeliver the contents of the lumen to the outer surface, for example, ina controlled or sustained fashion. The first segment includes a polymerselected from the group consisting of a hydrophilic, semi-permeableelastomer and a hydrophobic elastomer. Alternatively, the intravaginaldevice may include a solid first segment, which includes a hydrophilicsemi-permeable elastomer, an outer surface, and an aqueous lubricant,wherein the first segment is configured to deliver the aqueous lubricantto the outer surface. The devices may be an intravaginal ring, atampon-shaped device, or any other size and shape suitable for residencein a subject's vagina. Thus, when the device is placed in the subject'svagina, lubricant delivered to the outer surface of the device will beavailable for lubrication of vaginal tissues. The elastomer is notgelatin and does not dissolve in the vaginal environment.

As noted above, the first segment of the intravaginal device may includea hydrophilic, semi-permeable elastomer. Because such polymers aresemi-permeable, they allow the aqueous lubricant to slowly diffuse fromthe lumen to the outer surface of the device. No macroscopic channelssuch as slits or holes are necessary to deliver the aqueous lubricant indevices using such polymers to form the lumen and outer surface of thedevice. In illustrative embodiments, the hydrophilic elastomers arewater-swellable; e.g., in water they may swell up to 500% of their dryweight. In some embodiments, the hydrophilic elastomer of the deviceswells from about 20 wt % to about 500 wt % over its dry weight. Inother embodiments the hydrophilic elastomer swells from about 5 wt %,about 10 wt %, about 20 wt %, about 30 wt %, about 40 wt %, or about 50wt % up to about 100 wt %, about 150 wt %, about 200 wt %, about 300 wt%, about 400 wt % or about 500 wt % over its dry weight or over a rangeincluding any two such values. In still other embodiments, hydrophilicelastomers that swell to 600 wt %, 700 wt %, 800 wt %, 900 wt % or even1000 wt % may be used in those devices where mechanical integrity of thedevice is provided by other means including non-swellable or lowerswelling polymers. In certain embodiments, the hydrophilic elastomer issolid rather than having a lumen. In such devices, the matrix of polymerswells with absorbed lubricant such as glycerol or the aqueouslubricants disclosed herein.

Hydrophilic, semi-permeable elastomers useful in the present devicesinclude without limitation hydrophilic polyurethane, hydrophilicpolyether polyurethane, hydrophilic silicone polyurethane copolymer, andhydrophilic polyether polyamide. Hydrophilic polyurethanes are a classof thermoplastic or thermoset elastomers that may contain a mixture ofsoft blocks in the urethane that are both hydrophilic and hydrophobic.(See, e.g., Y. Gnanou, G. Hild, P. Rempp, “Hydrophilic polyurethanenetworks based on poly(ethylene oxide): synthesis, characterization, andproperties. Potential applications as biomaterials,” Macromolecules,1984, 17 (4), pp 945-952.) For example, the hydrophobic soft block maybe made from polyethylene oxide and the hydrophobic soft block may bepolytetramethylene oxide. These soft blocks can be mixed at certainratios known in the art to allow the polyurethane to absorb water andtherefore allow water and molecules to pass across the polyurethane.Even though the polyurethane is impregnated with water, the polyurethaneretains its elastomeric properties and can still function as acomfortable biomedical device. If the polyurethane is made from only ahydrophobic soft block such as polytetramethylene oxide, the resultingpolymer is almost impermeable to water and would not be useful in thedelivery of water slowly to vaginal cavity. In some embodiments,aliphatic diisocyanates form the urethane linkages between the blockcopolymers because aliphatic diisocyanates do not degrade into toxicaromatic diamines.

Hydrophilic polyurethanes include polyurethanes having ionomeric groupsin the backbone of the polyurethane such as, but not limited to,carboxylic acids. (See, e.g., CW Johnston, “Hydrophilic carboxypolyurethanes,” U.S. Pat. No. 4,743,673) Other ionomeric and watersoluble functional groups such as urea will allow water to be imbibedinto the elastomer and will allow the elastomer to swell. (See, e.g., FEGould, “Hydrophilic polyurethanes of improved strength” U.S. Pat. No.5,120,816.) In illustrative embodiments, the device includes ahydrophilic polyurethane selected from TECOPHILIC (a hydrophiliccopolymer urethane containing both polyethylene oxide andpolytetramethylene oxide soft blocks available from Lubrizol AdvancedMaterials, Inc., Cleveland, Ohio), HYDROTHANE (an aliphatic polyetherpolyurethane, available from AdvanSource Biomaterials Corp., Wilmington,Mass.), a hydrophilic styrene ethylene butylenes styrene block copolymeror hydrophilic styrene butadiene styrene block copolymer DRYFLEX(Elasto, Sweden), and polyether urethanes such as HYDROMED 640(AdvanSource Biomaterials Corp., Wilmington, Mass.). Such hydrophilicpolyurethanes may further include alkyl groups, polyethylene glycolgroups, fluoroalkyl groups, charged groups (e.g., carboxylic acids,amines and the like) or other chemical groups attached to the reactiveisocyanates attached to the ends of the polymer chains during synthesis(U.S. Pat. No. 5,589,563).

Hydrophilic silicone polyurethane copolymers are polymers that are amixture of polyether segments and polydimethylsiloxane rubber (PDMS)segments copolymerized in linear block copolymers that can be meltprocessed. In this class of polymers there will need to be added ahydrophilic group like polyethylene oxide or segments that containionomeric groups so that the normally hydrophobic nature of PDMS can becounteracted so the polymer can imbibe water and deliver it through thedevice membrane (U.S. Pat. No. 5,756,632). Preferred embodiments usealiphatic diisocyanates to form the block copolymers.

Hydrophilic polyether polyamides include PEBAX (Arkema, Inc., France)and polyether block amide copolymers. Polyether block amide copolymers,i.e. polyamidepolyether copolymers (PAEPC), are described in U.S. Pat.No. 4,361,680 (1982) to Borg et al; U.S. Pat. No. 4,332,920 (1982) toFoy et al; and U.S. Pat. No. 4,331,786 (1982) to Foy et al. Thesepolymers can be modified with enough hydrophilic groups likepolyethylene oxide to increase their hydrophilicity and allow them toabsorb water so it can be delivered through the device membrane or wall.

It will be understood by those of skill in the art that IVDs of thepresent technology may be manufactured using opacifiers, colors,fragrances and the like to tailor the appearance and smell of the IVDsas desired.

In some embodiments of the present devices that include a lumen, thefirst segment of the intravaginal device includes a hydrophobicelastomer. To allow delivery of the contents of the lumen to the outersurface, hydrophobic elastomers have at least one channel connecting thelumen to the outer surface. For example, the channels may be made byslits or holes through the elastomer forming the lumen and outer surfaceof the device. The slits or holes may be in any orientation on thedevice. In some embodiments the IVD is an IVR and the slits or holes onthe ring may be, e.g., parallel to or perpendicular to the ring axis.Such slits or holes may also be employed in IVDs (including IVRs) thatinclude hydrophilic elastomers. In some embodiments, at least onechannel is closed when the elastomer is in the relaxed state and openwhen the elastomer is under tension.

Any hydrophobic elastomers that can be formed into biomedical gradetubing may be used in the present devices including, without limitation(non-hydrophilic) polyurethane, silicone polyurethane, silicone(polydimethylsiloxane rubber, aka PDMS), and ethylene vinyl acetate(EVA). Flexible hydrophobic elastomers such as these are well-known inthe art. Suitable polyurethanes are described in Szycher's Handbook ofPolyurethanes and J. Biomater. Appl. 1999 14: 67. Another flexiblepolymer that useful in the present devices is silicone (SiliconeElastomers 2006, International Conference, 1st, Frankfurt, Germany, Sep.19-20, 2006 (2006), and Rubber Chemistry and Technology (2006), 79(3),500-519 and Pujol, Jean-Marc et al. and Edited by Marciniec, Bogdan eds.From Progress in Organosilicon Chemistry, Jubilee InternationalSymposium on Organosilicon Chemistry, 10th, Poznan, August, 1993 (1995),503-521). Another flexible polymer that useful in the present devices isethylene-vinyl acetate copolymer (Medical Plastics 2001, CollectedPapers of the Conference and Seminar, 15th, Copenhagen, Denmark, Sep.17-20, 2001 Pages 118-126 ISBN: 87-89753-38-0). Ethylene-vinyl acetatecomes in several hardness grades that increase in hardness as theethylene content increases. Therefore for soft and flexible vaginaldevices a softer grade of ethylene-vinyl acetate is preferred.

Lubricant delivered by intravaginal devices described herein may beaqueous or non-aqueous. The aqueous lubricant can be water, hypo-osmolarwater or solution, an aqueous solution, hyper-osmotic water or solution,iso-osmotic water or solution, and aqueous solution, or a gel. Forexample, the aqueous lubricant may be at least 90 wt % water or at least95 wt %, at least 96 wt %, at least 97 wt %, at least 98 wt % or atleast 99 wt % water, or essentially 100 wt % water. In some embodiments,the aqueous lubricant is iso-osmolar or hypo-osmolar and may includeions such as potassium, sodium, chloride and phosphate, e.g., at about0.1 wt % to about 0.25 wt %, about 0.5 wt % or about 0.75 wt %. Theaqueous lubricant may be buffered, optionally at an acidic pH to promotethe natural acidity of the vagina. Thus, the present aqueous lubricantsmay have a pH of about 3 to about 8, from about 3 to about 6 or fromabout 3.5 to about 4.5 or about 4. For example, the aqueous lubricantmay include vaginal fluid simulant, about 5 to about 50 mM lactic acid,an acetic acid buffer at a pH of about 3.5 to about 4.5 or to about 5.0,and optionally about 5 to about 50 mM glucose. In some embodiments, theaqueous lubricant may include vaginal fluid simulant, about 20 to about30 mM (or about 25 mM) lactic acid, a 10 mM to about 30 mM (or about 18mM) acetic acid buffer at a pH of about 3.5 to about 4.5 or to about 5.0and optionally about 20 to about 30 mM (or about 25 mM) glucose. Theaqueous lubricant may be free of steroids or may be free of any activepharmaceutical ingredient (i.e., those ingredients that have atherapeutic effect as opposed to a non-therapeutic biological effect).

Thus, the present aqueous lubricants may include water and a widevariety of additives such as, but not limited to, one or more salts,nonaqueous solvents (e.g., propylene glycol, glycerol), acids such asC1-8 carboxylic acids (i.e., carboxylic acids having 1-8 carbons suchas, e.g., lactic acid, acetic acid), glucose, antioxidants (e.g., BHT,ascorbic acid), preservatives (e.g. sorbital, sorbic acid, parabens,EDTA, sodium benzoate, tocopherol), surfactants (e.g. polysorbate 20 or60, sorbate salts), fragrance, flavoring agents, and sweeteners (e.g.saccharine, aspartamate). In addition, the lubricants may includepyridine, squalene, urea, complex alcohols, aldehydes, ketones, stearicacid, stearate, isopropyl palmitate, petrolatum, aloe barbadensis (AloeVera) leaf juice, cucumus sativus extract, helianthus annulus seed oil,soybean sterol, vitamin E acetate, vitamin A palmitate, provitamin B5,sodium acrylate/acryloyldimethyl taurate copolymer, dimethicone,glyceryl stearate, ceylalcohol, lecithin, mineral water, sodium PCA,potassium lactate, collagen, aminoacids, triethanolamine, DMDM,hydantoin, iodopropynyl, butylcarbamate, disodium EDTA, titaniumdioxide. The additives may be added at a concentration such that theaqueous lubricant is hypo-osmotic, hyper-osmotic or iso-osmolar incomparison to vaginal fluids or blood or tissue. By hypo-osmoticlubricant is meant that the osmolality of the lubricant is less thanthat of the vaginal fluid, or blood, or tissue fluid. In contrast, ahyper-osmotic lubricant has an osmolality that is greater than that ofthe vaginal fluid, or blood, or tissue fluid, while an iso-osmoticlubricant roughly matches the osmolality of the vaginal fluid, or blood,or tissue fluid.

Hyper-osmotic lubricants may be aqueous or non-aqueous. Such non-aqueouslubricants may be water-soluble (i.e., at least 1 mg/mL at 25° C.).Hyper-osmotic lubricants may be prepared from appropriate concentrationsof various agents including, but not limited to, glycerol, polyethyleneglycol, propylene glycol, carrageenan (i.e., sulfated polysaccharides),other lubricating or hydrating substances, salts, and hyper-osmoticaqueous agents, and the like. Hyper-osmotic may lubricants include,e.g., 100% glycerol or mixtures of water and glycerol such as at least 4wt %, about 4%, about 10 wt %, about 20 wt %, about 30 wt %, about 40 wt%, about 50 wt %, about 60 wt %, about 70 wt %, about 80 wt %, about 90wt %, about 91 wt %, about 92 wt %, about 93 wt %, about 94 wt %, about95 wt %, about 96 wt %, about 97 wt %, about 98 wt %, about 99 wt %glycerol, or ranges between and including any two such values.Hyper-osmotic lubricants may also include, e.g., 100% propylene glycolor mixtures of water and propylene glycol such as about 3 wt %, about 10wt %, about 20 wt %, about 30 wt %, about 40 wt %, about 50 wt %, about60 wt %, about 70 wt %, about 80 wt %, about 90 wt %, about 91 wt %,about 92 wt %, about 93 wt %, about 94 wt %, about 95 wt %, about 96 wt%, about 97 wt %, about 98 wt %, about 99 wt % propylene glycol, orranges between and including any two such values. For example, thepresent intravaginal devices may contain or otherwise include (if solid)about 50 wt % glycerol to 99 wt % glycerol.

While not wishing to be bound by theory, it is believed that lubricantfrom an IVD placed in the vagina and filled with glycerol or otherappropriate hyper-osmotic agent diffuses down its concentration gradientfrom the IVD and into the vaginal space. Because there are potentiallytwo or more diffusing species (e.g., the osmotic agent in the device andthe physiologic fluid outside the device), co-diffusion of both of theseagents can occur leading to behavior that varies with time. The hyperosmotic device also attracts water from the vagina due to the lowconcentration of water in the device and thus a water concentrationgradient is present in the system. The hydrophilic elastomer of the IVDswells with water and releases glycerol, while still attracting waterinto the device. Once the glycerol is present in the vaginal lumen at aconcentration that is hyper-osmotic to blood, water diffuses from thebloodstream and hydrates the vaginal cavity along with the moisturizingeffect of the glycerol. An additional benefit may be that the waterabsorbed into the polymer that was initially attracted by the glycerol(or other hyper-osmotic agent) later may act as a hydration source thatcould be released in response to the moisture needs of the vaginalmucosa at a later time when all of the hypo-osmotic agent has diffusedfrom the IVD.

When the lubricant is an aqueous gel, it may include, e.g., water andone or more additives selected from the group consisting ofpreservatives or disinfectants (e.g., benzalkonium chloride,benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, calciumlactate, glycerin, glacial acetic acid, hibitane acetate, methylparaben, phenylethyl alcohol, potassium sorbate, propylene glycol,propyl paraben, sodium benzoate, sodium ethyl paraben, sodiumpropionate, sorbic acid, sorbital, tocopherol), thickening/gellingagents (e.g., agarose, aluminum magnesium silicate, carbomer, carbopol,carrageenans, dermatan sulfate, ethyl cellulose, silicon dioxide, guargum, hydroxyethyl cellulose, hydroxyethyl methacrylate, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,maltodextran, polyacrylamide, polycarbophil, polyethylene glycol,polyethylene oxide, pluronic/poloxamer, polyvinyl alcohol, sodiumalginate, sodium carboxymethyl cellulose, sodium hyaluronate, sucrose,xanthan gum), pH modifying agents (e.g., adipic acid, alkyl fumarate,aluminium sulfate, calcium acetate, calcium carbonate, calcium lactate,citric acid, glacial acetic acid, glutamic acid, glycine, hydrochloricacid, lactic acid, methionine, nitric acid, phosphoric acid, potassiumbitartarate, sodium dihydrogen citrate, sodium citrate, sodium dibasicphosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide,sodium lactate, sodium monobasic phosphate, stannous chloride, succinicacid, tartaric acid), surfactants/solubilizing agents (e.g., benzylalcohol, beta cyclodextrin, polyoxyethylene 20 cetyl ether, cremophor,piperazine hexahydrate, pluronic/poloxamer, polyoxyethylene laurylether, lecithin, polyoxyethylene stearate, polysorbates, polyvinylalcohol, silicone, sodium cetearyl sulfate, sodium lauryl sulfate,sorbate salts, sorbitan esters, stearic acid), antioxidants (e.g.,ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene,citric acid, EDTA, phosphoric acid, sodium ascorbate, sodiummetabisulfite, tartaric acid, tertiary butyl hydroquinone),emollient/emulsifier (e.g., acacia, allantoin, aluminium magnesiumsilicate, bentonite, bleached bees' wax, carbomer, polyoxyethylene 20cetyl ether, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetylpalmitate, cholesterol, choleth, colloidal silicon dioxide, cremophor,diglycol stearate, glycerin, glyceryl monostearate, glyceryl stearate,guar gum, hydrous lanolin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, isopropyl myristate, isopropyl palmitate, lactose, lanolin,lecithin, methyl cellulose, mineral oil, palm oil, polyoxyethylenelauryl ether, polyoxyethylene stearates, polyethylene glycol,pluronic/poloxamer, polysorbates, propylene glycol monostearate, octyldodecanol, sodium carboxymethyl cellulose, sodium lauryl sulfate, sodiummonobasic phosphate, sorbitan esters, spermaceti wax, stearic acid,stearyl alcohol, triethanolamine, petrolatum), sweetening agent (e.g.,aspartamate, dextrose, maltose, mannitol, saccharine, xylitol), perfumes(e.g., isopropyl palmitate) glucose, moisturizers (e.g., aloe vera),flavoring agents, The aqueous gel lubricant may also be a wateremulsion. The gel may be also in a dry form that is mounted on the ringand is hydrated in the vagina by the aqueous solution lubricant. In thiscase the dry gel may contain a probiotic. Probiotics are livemicroorganisms thought to be healthy for the host organism. According tothe currently adopted definition by FAO/WHO, probiotics are: “Livemicroorganisms, which when administered in adequate amounts confer ahealth benefit on the host for example Lactic acid bacteria (LAB) orLactobacillus.”

The amount of lubricant (including aqueous lubricant) that may bereleased by the present devices may vary. For example, the presentintravaginal devices may deliver 0.001 mg to about 1000 mg or even up to2000 mg of lubricant to the outer surface of the device per day. In someembodiments the amount of lubricant delivered may be at least about 0.01mg, about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg,about 50 mg, about 75 mg, about 100 mg, about 250 mg, about 500 mg,about 750 mg, about 1000 mg, or about 2000 mg per day or a range betweenor including any two of the foregoing values. Another aspect of thepresent technology provides that the rate of lubricant delivered willdepend on the amount of dryness or water content of the vaginalepithelium. If the vagina is wet, less lubricant will be released, andif it is dry, more will be released. This means that the amount oflubricant that is released will change over time after the initialrelease from the device. Functionally this is an on demand release ratebased on the water content of the vaginal epithelium.

Intravaginal devices of the present technology may have a first segmentthat includes a tube formed from the polymer and having two ends. Theends of the first segment may be joined to each other to form, e.g., anintravaginal ring. The intravaginal devices may further include one ormore additional segments, each of which comprises a polymer, an outersurface and optionally a lumen. The additional segments may containdifferent lubricants or other substances for delivery to the vagina. Forexample, a segment may contain an aqueous gel lubricant and anothersegment may contain an aqueous solution lubricant. Each additionalsegment may be separated from any adjacent segment by an polymer segmentor plug. In an illustrative embodiment, the polymer segment or plug maybe a hydrophobic polyurethane such as TECOFLEX or ethylene vinylacetate. In some embodiments, the polymer of the first segment isdifferent from the polymer of at least one additional segment. Forexample, the first segment may be a hydrophilic, semi-permeableelastomer and at least one additional segment may be a hydrophobicelastomer. In the present devices including more than one segment, thedevice may include one solid segment and one segment with a lumen. Insome embodiments the segment including the lumen includes an aqueous gellubricant. Such lubricant is delivered through perforations, slits orholes in the lumen segment. In some embodiments, the intravaginal deviceis refillable with aqueous lubricant.

The intravaginal devices of the present technology may be designed toinclude one or more release chambers (“pods”) for the release ofadditional lubricant(s) or other substances, including but not limitedto drugs, as described in U.S. Ser. No. 61/375,671, filed Aug. 20, 2010and entitled “Devices and methods for intravaginal delivery of drugs andother substances.” Thus, in some embodiments, the intravaginal devicefurther includes one or more pods loaded with an agent selected from thegroup consisting of drugs and probiotics such as, e.g., Lactobacillus,vitamins, and minerals. The pods may be located on the inner side of thering or the outer side of the ring (See, e.g., FIGS. 2C, 2F, 6, 8). Insome embodiments, the intravaginal device is an intravaginal ring havinga pillow ring on the inner side of the ring. In others, the pod containsan ovule (see, e.g., FIG. 7). The ovule is a lumen containing anon-aqueous solution lubricant surrounded by a gelatin coating thatdissolves when placed in the vagina. Such ovules are available as K-Y®Brand LIQUIBEADS (Johnson & Johnson Healthcare Products Division ofMcNeil-PPC, Inc., Skillman, N.J.).

The intravaginal devices of the present technology include a widevariety of designs. For example, the device may be an intravaginal ring.Such rings may have an outer diameter ranging from about 40 mm to about80 mm (e.g., from about 50 mm to about 70 mm, or about 60 mm). The ringmay further have a cross-sectional diameter ranging from about 3 mm,from about 5 mm, or from about 7 mm to about 10 mm or to about 12 mm,and/or an inner diameter of about 1 mm, about 2 mm, about 3 mm, about 4mm, or about 5 mm to about 6 mm, to about 8 mm, to about 10 mm, or toabout 11 mm (e.g., 8 mm). The walls of the ring may range in thicknessfrom about 0.3 mm to about 3 mm (e.g., about 0.5 to about 1 or about 2mm). The rings may be circular, oval, tear-drop shaped, hour-glassshaped or any other suitable shape for use in the vagina. The ring ordevice may have accordion-like folds that allow for extra capacity inthe lumen, but sufficient structural integrity to maintain its basicshape when filled with aqueous lubricant. The intravaginal rings anddevices of the present technology are flexible and may be constructed sothat a force of not more than 10N is sufficient to compress the ring ordevice by 10%, or in some embodiments, 25%. In certain embodiments, suchas, e.g., when the device is constructed from hydrophilic semi-permeableelastomers, the ring further comprises a spring configured to supportthe ring or any part thereof. The spring may be embedded in or insertedinto the ring and encircles at least one lumen of the ring.

The most common cause of vaginal atrophy is the decrease in estrogen,which happens naturally during perimenopause, and increasingly so inpost-menopause. However this condition can sometimes be caused by othercircumstances and can occur throughout a woman's lifetime. The symptomscan include vaginal soreness and itching, as well as painfulintercourse, and bleeding after sexual intercourse. The shrinkage of thetissues can be extreme enough to make intercourse impossible. The causeof vaginal atrophy is usually the normal decrease in estrogen as aresult of menopause. Other causes of decreased estrogen levels aredecreased ovarian function due to radiation therapy or chemotherapy,immune disorder, removal of the ovaries, after pregnancy, duringlactation, idiopathic, and because of the effects of variousmedications: (Tamoxifen (Nolvadex), Danazol (Danocrine),Medroxyprogesterone (Provera), Leuprolide (Lupron), Nafarelin(Synarel)).

Accordingly, in another aspect, the present technology provides methodsof lubrication, including administering an intravaginal device asdescribed herein to a female in need of vaginal lubrication. The devicemay deliver any of the lubricants described herein, including aqueous ornon-aqueous lubricants, e.g., water, aqueous solution, hypo-osmolarwater, iso-osmolar or hyper-osmotic solution. Where the lubricant isaqueous, it may be delivered to the vaginal tissue in the form of aliquid, a vapor or a combination of both. In some embodiments of themethods, the device delivers 0.001-1000 mg or even up to 2000 mg oflubricant to the outer surface of the device per day. Other amounts oflubricant may be delivered as described herein. The lubricant may bedelivered over any period of time ranging from 1 hour to 1 month. Thus,the period that the lubricant is delivered may range from 1, 2, 3, 4, 5,10, 18, or 24 hours, or may range from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30 or 31 days. The intravaginal device may be administered to thefemale to relieve vaginal dryness from vaginitis, inflammation of thevagina (and the outer urinary tract) due to the thinning and shrinkingof the tissues, decreased lubrication, sexual arousal disorder,menopause, drug-induced vaginal dryness, dyspareunia, sexual paindisorder, menopause, pregnancy, hormone imbalance, anxiety and diabetes,or other related disorders.

The present technology in another aspect provides method of makingintravaginal devices as described herein. In one embodiment, where thedevice is solid, e.g., a solid hydrophilic elastomeric polymer, theelastomer may be injection molded or extruded. Where the intravaginaldevices are an intravaginal ring, the extrusion molding is joinedtogether by welding. The material is then swollen or loaded withlubricant into its final ring shape.

In some embodiments, the methods include adding a physiologicallyacceptable water-soluble ionic or non-ionic material to a lumen of anintravaginal device and exposing (e.g., soaking) the intravaginal devicein water, wherein the intravaginal device includes a first segmenthaving an outer surface and a lumen, wherein the first segment isconfigured to deliver the contents of the lumen to the outer surface,and the first segment comprises a hydrophilic, semi-permeable elastomer.The ionic material may include an alkali halide salt (e.g., NaCl, KCl)and/or other salts including but not limited to sodium acetate,potassium acetate, sodium phosphate, sodium hydrogen phosphate. Thenon-ionic material may include but is not limited to glycerol,polyethylene glycol, or propylene glycol.

Hyper-osmotic devices will be able to attract water or aqueous lubricantinto the ring internal lumen without puncturing the lumen. The time thismay take is between 1 and 24 hours depending on permeability of themembrane and the amount and nature of the osmotic attractant.

EXAMPLES Example 1 Single Segment Tubular IVR Constructed of HydrophobicElastomeric Tubing with Multiple Holes Containing Aqueous Gel Lubricant

A length of 6.5 mm outer diameter hydrophobic TYGON tubing (Saint-GobainCorp., Paris, France) with a 1 mm wall thickness was formed into a ringof diameter of ˜55-60 mm, by connecting the ends of the tubing with ahollow plug comprised of the same tubing material. The hollow plugdimensions were chosen as to connect the tubing ends to form a full ringstructure. Small holes were drilled into the tubing along the outerannulus of the ring at ˜1 cm spacings. Aqueous lubricant was loaded intothe lumen via a syringe needle. Application of external force this ring(such as that which may arise from the contraction and relaxation ofvaginal musculature), resulted in the expulsion of the lubricating gel(JUICY LUBE) in form of small pearls along the outer annulus of the ringas the gel migrated from the lumen through the holes and to the outersurface the tubular IVR. The same design may be constructed out ofsilicone or EVA medical grade tubing.

Example 2 Single Segment Tubular IVR Constructed of HydrophobicElastomeric Tubing with Multiple Slits Containing Aqueous Lubricant

A ring of similar dimensions and construction as described in Example 1was formed, however slits rather than holes were spaced along the innerannulus of the ring, parallel to the central ring axis. Lubricating gel(JUICY LUBE, ID LUBRICANTS, Westridge Laboratories, Inc., Santa Ana,Calif.) was loaded into the lumen via a syringe needle. Application ofexternal force to ring results in the expulsion of the lubricating gelfrom the lumen through the slits to the outer surface of the innerannulus of the tubular IVR. In this design, the slits are in compressionand thus closed unless a force (such as that which may arise from thecontraction and relaxation of vaginal musculature) is applied to theIVR. It will be understood that slits perpendicular to the ring axis mayalso be placed on the inner annulus of the ring or that slits may beplaced on the outer annulus of the ring in any orientation.

Example 3 Single Segment Tubular IVR Constructed of Hydrophilic,Semi-Permeable Elastomeric Tubing Containing Water

A tubular IVR was created employing TECOPHILIC HP-93A-100 tubing.TECOPHILIC HP-93A-100 is made of a hydrophilic, semi-permeableelastomeric polyurethane that swells to 100% of its weight when placedin water. A length of this tubing was submersed in water and the twoends of the tubing were connected each other using a connector made frompolyethylene tubing that has an outer diameter that is slightly largerthan the inner diameter of the TECOPHILIC tubing while still submersedin water to form a ring. When removed from the water, the water-swelledring contained approximately 5 mL of water within the lumen. Thewater-swelled ring had an outer diameter of ˜60 mm with a tubing outerdiameter of ˜8 mm. The wall thickness of the water-swelled tubing wasestimated to be ˜2 mm. Excess water from on the surface of the ring wasremoved. A line drawing of the ring is shown in FIG. 3. The surface thering continued to remain moist as a result of permeation of the waterfrom the lumen through the polyurethane to the outer surface of thering. When the water-filled polyurethane ring was placed in contact withskin, a moisturizing and hydrating effect was noted. Over several days,air bubbles became visible in the lumen as a result of pressureequalization due to the continued water migration from the lumen,through the microporous holes of the polyurethane tubing and subsequentevaporation from the outer surface of the ring.

Example 4 Two Segment Tubular IVR Constructed of a Hydrophilic,Semi-Permeable Elastomeric Segment Containing Water and a HydrophobicElastomeric Segment with Multiple Holes Containing a Gel Lubricant

To create the first segment, a first length of a hydrophobic tubing madeout of TYGON, approximately 50 mm long with an outer diameter of 7 mmwas plugged at each end using a small plug of molten polyurethane. Suchplugs were employed to prevent/mixing of the contents upon connectingthe first segment to the second segment. A second segment was created bytaking a second length of tubing made of TECOPHILIC HP-93A-100, ahydrophilic, semi-permeable polyurethane elastomer. The ends of thefirst segment were connected to the ends of the second segment usingappropriately sized hollow polypropylene tubing connectors to form aring. Two holes, approximately 1 mm in diameter were placed parallel tothe ring axis in the first segment. The first segment was filled withgel lubricant using a syringe. The second segment was filled with water,also using a syringe. The two segment tubular IVR thus constructedreleased both a small amount of vaginal lubricant as well as aqueouslubricant over a period of time.

Example 5 Two Segment Tubular IVR Constructed of a Hydrophilic,Semi-Permeable Elastomeric Segment Containing Water and a HydrophobicElastomeric Segment with Multiple Holes Containing Vaginal Lubricant

As a variation to Example 4, two holes, approximately 1 mm in diameterwere drilled perpendicular, rather than parallel, to the ring axis. Asimilar effect was achieved as in Example 4.

Example 6 Collapsible Hydrophobic Tubing

The IVR in Example 5 may be modified by employing hydrophobic tubing,which has small holes and is collapsible under vaginal pressure. Suchpressure provides the force necessary to expel the vaginal lubricantfrom the lumen through the holes and to the outer surface the tubularIVR.

Example 7 Collapsible Hydrophobic Tubing with a Support Band

The IVR in Example 1 may be modified by incorporation of a band offlexible spring material (e.g., nylon or spring steel) into the ring,providing support to the ring as well as a retractive force useful forretention of the ring in the vaginal canal.

Example 8 Membrane-Containing IVRs, Structurally Supported

In one example the water-swellable tubing is made thin, at a wallthickness of, but not limited to, 0.1 mm to 3 mm to allow for deliveryof the aqueous solution lubricant. This thin structure may not be strongenough to provide a counterbalancing force to keep the ring in thevaginal canal. Therefore, the water-swellable tubing can be stiffenedusing a number of support-structures that are well known in the art. Inone aspect, the water-swellable tubing is extruded at a cross sectionaldiameter of, but not limited to, 2 mm to 10 mm and is wrapped with fibermesh support-structure and then jacketed with another layer of moltenwater-swellable tubing. In another embodiment the water-swellable tubingof cross sectional diameter of, but not limited to, 2 mm to 10 mm isjacketed over a spring or a metal mesh support-structure that is made ofmaterials including but not limited to titanium, KEVLAR, nylon, carbonfiber, stainless steel or other spring like materials or polymers thatcan be jacketed in a jacketing mold tool. The resulting water-swellabletubing when formed into ring would have a force to compress the IVR 10%of its initial outer diameter of, but not limited to, approximately 0.25to 10 N. The resulting tube is cut into the correct length of, but notlimited to, approximately 10 to 30 cm and formed into a ring by directlywelding the water-swellable tubing ends together. In another aspect, aconnector is used form a rings from the length of water-swellabletubing. The connector is a part that either jackets the water-swellabletubing or is inserted into the water-swellable tubing. The connector iswelded into the water-swellable tubing making an intact and aqueoussolution lubricant tight device where the aqueous solution lubricant isnot leaking through the connection of the two ends of thewater-swellable tubing. The weld is made by solvent welding, heatwelding, induction welding, butt welding, or other thermoplastic weldingtechniques well known to those skilled in the art. The device is dry atthis point and is filled with the aqueous solution lubricant.

In one example of filling, the aqueous solution lubricant is filled intothe device at a volume of, but not limited to, 1 to 12 mL, via a syringeor similar filling apparatus that enters the device through a port builtinto the connector that reseals after the syringe is removed. In anotherembodiment the aqueous solution lubricant filling port is mounted in thewater-swellable tubing.

Example 9 IVD with Check Valves

In another example the device with a thin wall would collapse due to thereduced amount of aqueous solution lubricant in the core of the deviceafter being placed in the vagina. This problem is alleviated by adding asupport-structure to the water-swellable elastomer of the device. Inanother example, a check valve that allows gasses into the device, butdoes not allow appreciable water out of the ring through the checkvalve, is formed into the device. In one example the check valve isassembled into the connector that connects the two ends ofwater-swellable tubing together in a torus shape (i.e., an IVR). Inanother example the check valve is mounted into the water-swellabletubing. In still another example, a piece of gas permeable membranee.g., GORE-TEX is mounted in the connector and allows air into thedevice after aqueous solution lubricant is released. In a furtherexample, the gas permeable membrane is mounted on a hole that is formedin the water-swellable tubing.

Example 10 Rigidification of Hydrophilic Tubing

In one example the water-swellable tubing is thin, at a wall thicknessof, but not limited to, 0.1 mm to 3 mm to allow for delivery of theaqueous solution lubricant. This thin structure may not be strong enoughto provide a counterbalancing force to keep the device in the vaginalcanal. Therefore, the water-swellable tubing can be stiffened using anumber of support-structures that are well known in the art. In oneaspect, the water-swellable tubing is extruded at diameter of, but notlimited to, 2 mm to 10 mm and wrapped with fiber mesh support-structureand then jacketed with another layer of molten water-swellable tubing.In another embodiment the water-swellable tubing is jacketed over aspring or a metal mesh support-structure that is made materials,including but not limited to, titanium, KEVLAR, nylon, carbon fiber,stainless steel or other spring like materials or polymers that can bejacketed in a jacketing mold. The resulting water-swellable tubing whenformed into ring would have a force to compress the IVR 10% of itsinitial outer diameter of, but not limited to, 0.25 to 10 N. Theresulting tube is cut into the correct length of, but not limited to,approximately 10 to 30 cm and formed into a ring by directly welding thewater-swellable tubing ends together.

In one embodiment the lumen of the device of this example is filled withwater. In another embodiment, a gel forming formulation is attached toor inserted in the ring. The gel forming formulation includes polymerssuch as, but not limited to, hydroxyethyl cellulose, carrageenans,dermatan sulfate, hydroxypropyl cellulose, polyethylene oxide, methylcellulose. The gel forming formulation may also include lanolin, aloevera, moisturizers, preservatives, vitamins and probiotics or otheragents known to those skilled in the art. One aspect uses a connectorthat is attached on the end of the water-swellable tubing and is used toform a torus from the length of water-swellable tubing. The connector isa part that either jackets the water-swellable tubing or is insertedinto the water-swellable tubing. In another aspect, the connector hasattached to it the ability to hold a compressed pellet of gel formingformulation. The connector is welded into the water-swellable tubingmaking an intact and aqueous solution lubricant tight device where theaqueous solution lubricant is not leaking through the connection of thetwo ends of the water-swellable tubing. The weld is made by solventwelding, heat welding, induction welding, butt welding, or otherthermoplastic welding techniques well known to those skilled in the art.The device is dry at this point and is filled with the aqueous solutionlubricant.

Example 11 Dual Reservoir IVR Device

An IVR was constructed containing two separate reservoirs. One reservoirwas made from a hydrophilic polymer and the other from a hydrophobicpolymer with pores in the elastomer. These separate reservoirs can beused to hold and release different liquids/lubricants. The first segment(hydrophilic polymer) delivered the aqueous or non-aqueous solutionlubricant and the second segment (hydrophobic polymer) delivered theaqueous gel lubricant. The aqueous gel lubricant is delivered throughpores in the tubing wall.

In this example, the device was fabricated from an 80 mm length ofTECOFLEX EG-85A tubing segment (5.5 mm cross-section×1.5 mm wallthickness) and an 80 mm length of hydrophilic aliphatic thermoplasticpolyurethane tubing segment (5.5 mm cross-section×0.7 mm wallthickness). The ends of the TECOFLEX segment were sealed using aPlasticWeld Systems, Inc. (Newfane, N.Y.) bonding die (HPS-EM; preheat10 seconds, heat 11 seconds, cool 15 seconds, power 16%, travel distanceof 3 mm). After sealing the ends, a 0.5 mm drill bit was used to drillholes along one side of the sealed tube, approximately every 3 mmstarting and ending 20 mm from each end to give 20 holes. These holeswere only drilled into one wall of the tube, forming a channel from theinner lumen to the surface of the tube. In other embodiments the holescan be drilled all around the rod axially so that the holes point inmany directions. In another embodiment, this design can be configured asa tampon-like device. The ends of the hydrophilic aliphaticthermoplastic polyurethane segment were sealed using a bonding die(HPS-EM). By placing the clamp 9 mm from the die opening, a 6 secondpreheat cycle was followed by a 7 second heat cycle with a 10 secondcooling cycle following. The ends of each segment were joined togetherusing an induction welder split die (HPS-20). The ends were placed intothe die, clamped, and subjected to a 25 second cycle at 50% powerfollowed by a 12 second soak and a 20 second cooling cycle, resulting inthe joining of the ends and then repeated to form the ring. Duringwelding, the pores in the TECOFLEX segment were configured to place thedrilled holes along the inner annulus of the IVR. The IVRs were annealedat 65° C. for 5 minutes and cooled at 10° C. for 20 minutes. A 27 gaugeneedle was inserted along the inner annulus of the IVR through the jointand into the lumen of the TECOPHILIC side. Another needle was insertedinto the lumen on the other side of the joint and a 3 mL syringe wasused to inject 0.5 grams of water into the IVR until the liquid startedto emerge out of the other needle, thus filling the TECOPHILIC side ofthe IVR device. After soaking the IVR for 1 day in 100 mL of water, a 27gauge needle and 3 mL syringe was used to inject the lumen of theTECOFLEX side with 0.1 grams of a 0.2 wt % methylene blue/K-Y® BrandJelly (Johnson & Johnson Healthcare Products Division of McNeil-PPC,Inc., Skillman, N.J.) mixture.

In another aspect, the devices described above can be made via amultistep injection molding process where the water swellable tubing isformed into the device by methods well known to those skilled in theart.

Example 12 IVRs of Varying Shapes

The shapes of any of the IVRs of present technology can be modified asto promote increased comfort and/or to promote increased contact withthe vaginal canal. For instance, the IVR may be deformed or changed froma toroid shape. Indeed, any of the examples listed are readily adaptableto cylindrical shape such as that of a tampon (see Examples 40-41below). In one aspect, the IVR is shaped similar to an “accordion” or“bellowed” to increase the surface area of the tubing that is in contactwith the vaginal epithelium. In another aspect, the shape of the IVR iselliptical, which increases comfort for the patient. In another aspect,the pods or cores are located on the outer portion of the IVR, ratherthan on the inner portion of the IVR. The concept of the pods or coreson the IVR are the addition of one or two or more pods or cores attachedto or inserted into the IVR. The pods or cores deliver substances suchas carrageenans simultaneously with the aqueous solution lubricant. Inanother aspect, the ring is bent out of plane to be curved, which mayincrease comfort to the patient and increase the surface area in contactwith the vaginal epithelium. In a further aspect, the ring is the shapeof an “hour-glass,” which also increases the comfort to the patient. Infurther aspect, the IVR is prepared in the shape of a circle, withadjoining “pillows” on four sides of inner portion of the ringcontaining a greater quantity of aqueous solution lubricant. Thedimensions of the ring are approximately 60 mm in total diameter. Theouter portion of the ring containing the aqueous solution lubricant is 3to 10 mm in diameter, and the diameter is approximately 7 mm of swollenpolymer tubing. Adjoining pillows attached to four sides of the innertubing are up 10 to 25 mm inward from the outer edge of the tubing. Thiswould leave up to 10 mm of hollow space in the center of the “pillowed”IVR for fluid lubricant.

Example 13 Method of Insertion

In yet another aspect, the device is inserted into the vagina using adevice or ring applicator (WO/1999/038468 and U.S. Pat. No. D442,688) orfeminine product applicators similar to those supplied with tampons andlubricant or moisturizer products.

Example 14 Acidifying Agents in the IVR

One example of the IVR includes pH modifying agents (e.g., adipic acid,alkyl fumarate, aluminium sulfate, calcium acetate, calcium carbonate,calcium lactate, citric acid, glacial acetic acid, glutamic acid,glycine, hydrochloric acid, lactic acid, methionine, phosphoric acid,potassium bitartarate, sodium dihydrogen citrate, sodium citrate, sodiumdibasic phosphate, sodium carbonate, sodium bicarbonate, sodiumhydroxide, sodium lactate, sodium monobasic phosphate, succinic acid,tartaric acid) in the aqueous lubricant to promote the natural acidityof the vagina.

Example 15 Continuous Release of Aqueous Lubricant

An IVD of the present technology, e.g., an IVR, is administered to awoman in need of or desiring and a sufficient amount of the aqueousand/or non-aqueous lubricant (including, e.g., gel lubricant) isreleased continuously over 24 to 72 hours or up to including 5 to 7 daysor up to 30 days to provide relief from vaginal dryness or vaginaldiscomfort. In another aspect, a sufficient amount of the aqueouslubricant (and gel lubricant) is released continuously over severalminutes to several hours (up to 24 hours) to provide relief of vaginaldryness or vaginal discomfort. In another aspect, a sufficient amountthe aqueous lubricant and gel lubricant is released continuously overseveral days (3 to 7 days) to provide relief of vaginal dryness orvaginal discomfort. In another aspect, the aqueous solution lubricantand gel lubricant is released in such a manner that it would providesufficient relief of vaginal dryness or vaginal discomfort and be usedas needed on an as needed basis from several minutes to several days.The IVD remains in place from several minutes to several days and isremoved when the woman determines she has sufficient relief, or wearsfor as long as desired for up to several days.

Example 16 Solid Polymer Matrix IVR Constructed of TECOPHILICSP-80A-150 1. Extrusion of TECOPHILIC SP-80A-150

Hydrophilic polymer TECOPHILIC SP-80A-150 (Lubrizol Advanced Materials,Inc., Cleveland, Ohio) was extruded to form polymer rods using methodsknown to those skilled in the art. Briefly, a Brabender (C. W. BrabenderInstruments, Inc., South Hackensack, N.J.) single screw extruder wasused to extrude approximately 200 g of TECOPHILIC SP-80A-150 (dried to0.077% water) through a 4.5 mm rod die to give a rod of 5.5 mmcross-section. The temperatures were T1=125° C., T2=120° C., T3=120° C.,T4=115° C. with a screw speed of 25 rpm.

2. Procedure for Preparing TECOPHILIC SP-80A-150 IVR Device

A matrix IVR was constructed that is capable of holding various fluidsusing water-swellable polymers that can hydrate (swell) up to but notlimited to 150% of its dry mass, such as with TECOPHILIC SP-80A-150.Rods of TECOPHILIC SP-80A-150 (5.5 mm cross-section) were cut to 110 mmand the ends were joined by induction welding using a split die welder(HPS-20) settings of 45% power for 25 seconds followed by an 18 secondsoak and 20 second cool. After the joint was completed, it was allowedto cool for 10 minutes on the inside of a small beaker to support thecooling joint. After overnight storage, the rings were annealed to makethe device circular by: 1) securing the rings around the cylindricalneck of a 125 mL Erlenmeyer flask and heating in a convection oven at80° C. for 5 minutes, then air cooled at room temperature for 10minutes.

3. Procedure for Preparing Iso-Osmolar Matrix IVR Device

A matrix IVR loaded with iso-osmolar fluid was prepared as follows.TECOPHILIC SP-80A-150 intravaginal rings (IVRs) were placed in 100 mL of100 mM acetate buffer, containing 30 mM NaCl (pH 5, 305 mOsm) for 4 daysto swell the polymer to equilibrium.

4. Procedure for Preparing Hypo-Osmolar Matrix IVR Device

A matrix IVR loaded with a hypo-osmolar fluid was prepared as follows.TECOPHILIC SP-80A-150 IVRs were placed in 100 mL of distilled de-ionized(DDI) water for 4 days to swell the polymer to equilibrium.

5. Procedure for Preparing Hyper-Osmolar Matrix IVR Device

A matrix IVR loaded with a hyper-osmolar fluid was prepared. TECOPHILICSP-80A-150 IVRs were placed in 100 mL of a 70/30% v/v mixture of 100 mMacetate buffer with 30 mM NaCl and 3.8 M glycerol (pH 5, 428 mOsm) for 4days to swell the polymer to equilibrium. Alternatively, glycerol couldbe replaced with propylene glycol.

6. Procedure for Preparing VFS Matrix IVR Device

A matrix IVR loaded with vaginal fluid simulant (VFS) was prepared asfollows. To prepare 1 L of VFS, the following were combined: 5 g ofglucose, 3.51 g of NaCl, 2.0 g of lactic acid, 0.4 g of urea, 0.222 g ofcalcium hydroxide, 0.16 g of glycerin, 0.02 g of bovine serum albumin, 1g of glacial acetic acid, and 1.4 g of potassium hydroxide were added toDDI water. Subsequently, 5 mL of 1 M HCl was added to bring the pH to4.21 and DDI water was then added to a 1 L volume. A TECOPHILICSP-80A-150 IVR was placed in 100 mL of VFS for 3 days to swell thepolymer to equilibrium with 3.2 mL of VFS.

Example 17 Hydrophilic Silicone Polyurethane Matrix IVR

The purpose of the following prototype was to construct an IVR out of asilicone material. In this embodiment, segments of hydrophilic siliconepolyurethane (DSM Biomedical, Berkeley, Calif.) rod were cut to 155 mm(5.2 mm cross-section). The ends were joined by butt welding thesegments together (max power, 8 second melt time) to form a ring. Theresultant flashing was removed from the polymer ring after curingovernight.

Example 18 TECOPHILIC HP-93A-100 Matrix Device with Pod Holder

An IVD was constructed combining a swellable polymer matrix IVR with anon-swellable elastomeric section to hold a pod. A pod is a polymericchamber that has at least one orifice through which a formulation isreleased when in contact with the vaginal cavity. The chamber contains asustained release formulation, wherein the formulation includes awater-swellable polymer and an intravaginally administrable substance.By “sustained release formulation” is meant a formulation of theintravaginally administrable substance that is released over the courseof a period of one or more hours up to several days. A 30 mm segment,including the pod holder, was cut out of an injection moldedTECOFLEXEG-85A pod holder. A TECOPHILIC HP-93A-100 rod (cross-section4.6 mm) was cut to 105 mm. The TECOPHILIC polymer segment was annealed,to form a ring shape with high circularity at 70° C. for 5 minutesinside of a 100 mL beaker, and then cooled at room temperature (RT) for15 minutes to provide initial curvature to the segment. A ring wasformed by butt-welding (max power, 8 seconds of melting) the ends of theTECOPHILIC rod to the ends of the TECOFLEX pod holder segment.

Example 19 TECOPHILIC HP-93A-100 Reservoir Device with Pod Holder

The present device combines a swellable reservoir IVR with anon-swellable section to hold a pod. An injection molded TECOFLEX EG-85Apod holder IVR was cut in half so each half included a pod holder andwas 80 mm in length. TECOPHILIC HP-93A-100 tubing (cross-section of 4.8mm and wall thickness of 250 μm) was cut to 76 mm. A stainless steelspring (4.01 mm cross-section, 0.51 mm wire diameter, 3 coils/cm) wascut to 80 mm. 5 mm of the Tecophilic tubing was overlapped onto theTECOFLEX rod and then wrapped in a 5 mm wide, 80 mm long piece ofaluminum foil to increase the cross-section to 5.5 mm. The joint wasplaced in an induction welder at 45% power for 25 seconds followed by an8 second soak and a 10 second cool to join the tubing to the rod. Thespring was inserted into the tube and compressed so the other end of thetube could be overlapped onto the rod and the procedure from above wasrepeated to form a ring. Removal of the aluminum foil resulted in acomplete IVR.

Example 20 Lactobacillus Pods

In the present example, pods were constructed out of acrylonitrilebutadiene styrene (ABS) for the purpose of holding and releasing pelletsmade of materials such as Lactobacillus. The pods were inserted intomatrix and reservoir IVDs having pod holders (described above inExamples 18 and 19). Pellets were made from powder contained in NaturalFactors (Coquitlam, BC, Canada), Multi Acidophilus capsules.Approximately 170 mg of the powder was pressed into a pellet of 4.6 mmheight×6 mm diameter for 1.5 minutes at 5000 lbs of pressure using amanual bench top press (Carver Inc., Wabash, Ind.). ABS pods werefabricated on a lathe by using ¼ inch ABS rod stock with interiordimensions of 5.8 mm height and a diameter of 6.5 mm. The pellets wereinserted into these pods and ABS lids or caps with a 1.5 mm orifice wereglued onto the pods using ABS cement, which sealed the pellet inside. Apod was inserted into a matrix pod holder and a reservoir pod holder forrelease studies

Example 21 IVR with Matrix Pod Holder and 100% Lactobacillus Pellet

An IVR was constructed that combines a water-swellable section and anon-swellable section holding and releasing a Lactobacillus pellet. ATECOPHILIC HP-93A-100 matrix pod holder IVR (described earlier) wasused. Approximately 170 mg of the inside powder from Natural FactorsMulti Acidophilus capsules was pressed into a pellet of 4.6 mm height×6mm diameter for 1.5 minutes at 5000 lbs of pressure using a manual benchtop press. A Lactobacillus pellet (6 mm in diameter×4.6 mm in height,0.1717 g) was glued into a circular hole in the elastomer made byinjection molding using the TECOFLEX 1-MP adhesive. Only one of theexposed, circular sides of the cylindrical pellet was coated with glue.An identical device has been fabricated with a removable adhesive stripcovering the pellet to prevent leaking or dispensing of the contents inthe device prior to use.

Example 22 HPC/Lactobacillus Pellet/Pod

An IVR was constructed that can release Lactobacillus from a pod. Thepod was made out of ABS and holds and releases material that is in theform of a pellet composed of a HPC/Lactobacillus mixture. In thisembodiment, pellets were made by combining Klucel GF Pharm hydroxypropylcellulose (HPC) (Hercules Inc., Wilmington, Del.) with the powderobtained from Natural Factors Multi Acidophilus capsules (50/50 wt %).Approximately 170 mg of the powder was pressed into a pellet of 4.6 mmheight×6 mm diameter for 1.5 minutes at 5000 lbs of pressure using amanual bench top press. The pellets were inserted into ABS pods withinterior dimensions of 5.8 mm height and 6.5 mm diameter. ABS lids, witha 1.5 mm orifice were glued onto the pods using an ABS cement to sealthe pellet inside. A pod was inserted into a matrix pod holder (ofExample 18) and reservoir pod holder (of Example 19) for releasestudies. An identical device has been fabricated with a removableadhesive strip covering the pod to prevent leaking or dispensing of thecontents in the pod prior to use.

Example 23 HEC Pellet/Pod Device

In the present example, pods were constructed out of ABS for the purposeof holding and releasing pellets made of materials such as hydroxyethylcellulose (HEC) lubricant were constructed out of ABS. Pellets were madefrom 1 wt % Rhodamine B Isothiocyanate-Dextran and 99 wt % Natrasol™ 250HX hydroxyethyl cellulose (HEC). Approximately 170 mg of the powder waspressed into a pellet of 4.6 mm height×6 mm diameter for 1.5 minutes at5000 lbs of pressure using a manual bench top press (Carver Inc.,Wabash, Ind.). Pellets also were made from 100 wt % Natrasol™ 250 HXhydroxyethyl cellulose using an identical method. The pellets wereinserted into ABS pods with interior dimensions of 5.8 mm height and 6.5mm diameter. ABS lids with a 1.5 mm orifice were glued onto the podsusing an ABS cement to seal the pellet inside. A pod was inserted into amatrix pod holder (of Example 18) and a reservoir pod holder (of Example19) for release studies. An identical device has been fabricated with aremovable adhesive strip covering the pellet to prevent leaking ordispensing of the contents in the device prior to use.

Example 24 K-Y® Brand LIQUIBEADS® in Matrix Pod Holder Device

In the present example, a glycerin ovule such as the K-Y® BrandLIQUIBEADS® ovule was mounted in a matrix pod holder IVR. A TecophilicHP-93A-100 matrix pod holder IVR (of Example 18) was used. The podholder was stretched over a 10 mm Allen Wrench and annealed in an ovenfor 5 minutes at 100° C. The pod holder was then stretched over a 5 mLscintillation vial and placed in the oven for 5 minutes at 100° C. Aftercooling at room temperature for 20 minutes, a KY® Brand LIQUIBEADS®ovule was inserted into the pod holder.

Example 25 TECOPHILIC HP-60D-35 Reservoir Device Filled with Glycerol

A reservoir IVR filled with glycerol was constructed as follows. Theintravaginal rings were constructed using hydrophilic aliphaticthermoplastic polyurethane TECOPHILIC HP-60D-35 tubing with across-section of 4.8 mm and a wall thickness of 1.10 mm. The tubing wascut to a length of 170 mm and both ends were sealed using a tip-formingdie. Since the cross-section of the tubing was smaller than the 5.5 mminner diameter of the bonding die clamps, the air that pressurizes theclamps was disabled The unpressurized clamps were still used to supportand guide the tubing into the die. By placing the clamp 1 cm from thedie opening, a 10 second preheat cycle was followed by an 11 second heatcycle, with the tubing manually fed into the die opening after the 10second preheat cycle. A 15-second cooling cycle followed and resulted ina 2-3 mm tip. After sealing both ends, an induction welder was used tojoin the ends together to form a ring. The ends were placed into thedie, clamped, and subjected to a 27 second cycle at 45% power, which wasfollowed by an 18 second soak and a 15 second cooling cycle.Alternatively, glycerol could be replaced with propylene glycol.

Example 26 Hydrophilic Thermoplastic Aliphatic Polyurethane LumenDevices (0.7 mm Wall Thickness)

A reservoir IVR constructed out of hydrophilic thermoplastic aliphaticpolyurethane (DSM Biomedical, Berkeley, Calif.), similar to TECOPHILICHP-60D-35 (5.5 mm cross-section×0.7 mm wall thickness) was cut to 169 mmand the ends sealed using a bonding die (HPS-EM; preheat 6 seconds, heat7 seconds, cool 10 seconds, power 20%, travel distance of 9.0 mm). Aftersealing, the ends were welded together using an induction welder (25seconds of 55% power, 15 second soak, 15 second cool). After curingovernight, two 27 gauge needles were inserted through the joint into thelumen. In another embodiment the syringe needles were inserted throughthe inside wall of the torus, which is under compression. A syringefilled with various liquids described in Examples 28, 29 and 31 belowwas used to fill the lumen with the mixture through one syringe needles.In one embodiment TECOFLEX 1-MP adhesive was used to seal the syringeneedle holes after filling.

Example 27 Hydrophilic Thermoplastic Aliphatic Polyurethane LumenDevices (1.5 mm Wall Thickness)

A reservoir IVR constructed out of hydrophilic thermoplastic aliphaticpolyurethane, similar to TECOPHILIC HP-60D-35 (5.5 mm cross-section×1.5mm wall thickness) was cut to 169 mm and the ends sealed using a bondingdie (HPS-EM; preheat 10 seconds, heat 11 seconds, cool 15 seconds, power16%, travel distance of 4.0 mm). After sealing, the ends were weldedtogether using an induction welder (25 seconds of 55% power, 15 secondsoak, 15 second cool). After curing overnight, two 27 gauge needles wereinserted through the joint into the lumen. In another embodiment thesyringe needles were inserted through the inside wall of the torus,which is under compression. A syringe filled with various lubricants asdescribed in Examples 30 and 32 below was used to fill the lumen withthe mixture through one syringe needles. In one embodiment TECOFLEX 1-MPadhesive was used to seal the syringe needle holes after filling.

Example 28 70 wt % Glycerol/30 wt % Water Hydrophilic ThermoplasticAliphatic Polyurethane (0.7 mm Wall Thickness) Reservoir Device

A reservoir IVR containing a mixture of glycerol and water wasconstructed as described. The device from Example 26 was filled with a70/30 wt % water/glycerol mixture using the syringe method from Example26. Alternatively, glycerol could be replaced with propylene glycol.

Example 29 100% Glycerol-Filled Hydrophilic Thermoplastic AliphaticPolyurethane (0.7 mm Wall Thickness) Reservoir Device

A reservoir IVR containing glycerol was constructed as described. Thedevice from Example 26 was filled with 100% glycerol using the syringemethod from Example 26.

Example 30 100% Glycerol-Filled Hydrophilic Thermoplastic AliphaticPolyurethane (1.5 mm Wall Thickness) Reservoir Device

A reservoir IVR containing glycerol was constructed as described. Thedevice from Example 27 was filled with 100% glycerol using the syringemethod from Example 27.

Example 31 DDI Water-Filled Hydrophilic Thermoplastic AliphaticPolyurethane (0.7 mm Wall Thickness) Reservoir Device

A reservoir IVR containing DDI water was constructed as described. Thedevice from Example 26 was filled with DDI water using the syringemethod from Example 26.

Example 32 DDI Water-Filled Hydrophilic Thermoplastic AliphaticPolyurethane (1.5 mm Wall Thickness) Reservoir Device

A reservoir IVR containing DDI water was constructed as described. Thedevice from Example 27 was filled with DDI water using the syringemethod from Example 27.

Example 33 Remote Loaded NaCl Reservoir Device

A reservoir IVR filled with water and fabricated without puncturing orperforating the wall of the device was constructed. IVRs was preparedusing tubing made from TECOPHILIC HP-93A-100 with a cross-section of 4.8mm and a wall thickness of approximately 250 μm cut to a length of 120mm. The same polymer in the form of a solid rod of 4.6 mm cross-sectionwas cut into 20 mm segments to be used as plugs to seal the tube. Oneplug was inserted 10 mm into one end of the tube and then 0.3784 and0.6873 grams of NaCl was placed into each device, respectively. Afterthe NaCl addition, the other end of the plug was inserted into the openend of the tube until the two ends of the tube were joined together,forming a closed system. An induction welder was used to join the endsof the tube together and join them onto the plug. The plug was placedinto the die, clamped, and subjected to a 25 second cycle at 45% powerfollowed by an 8 second soak and a 10 second cooling cycle. After curingovernight, the IVRs were placed in 250 mL of DDI water at 37° C. After 5days, the IVRs had increased in mass by approximately 2.5 grams and theinside was filled with the liquid. Sampling the remaining fluid exteriorto the IVR (filled with 0.6873 g of NaCl) after 7 days of soaking, theosmolality was found to be 62 mOsm, making this IVR hypo-osmotic toblood plasma. Adjusting the amount of NaCl added to the interior or theamount of water the IVR is placed in to soak, the final, equilibriumconcentration of NaCl is used to create a hyper-osmotic, iso-osmotic, orhypo-osmotic interior lumen of the IVR relative to the body.

Example 34 A 97/3 wt % Water/Glycerol Reservoir (Remote Loading Method)

An IVR filled with a mixture of glycerol and water loaded into the IVRwithout creating a hole in the membrane by puncturing with a syringe.IVRs were constructed using tubing made from TECOPHILIC HP-93A-100, witha cross-section of 4.8 mm and a wall thickness of approximately 250 μmcut to a length of 120 mm. To load the tubing with glycerol, 0.8 gramsof glycerol was placed into each sample of tubing along with a customcompression spring (120 mm long, 4.01 mm cross-section, 0.51 mm wire, 3coils/cm). A solid rod of TECOPHILIC HP-93A-100 of 4.6 mmcross-sectional diameter was cut into 20 mm segments to be used as plugsto seal the tube ends. A closed ring or tube is formed by inserting a 10mm polymer plug into the two open ends of the tubing and joining theends together. A 1 cm wide×80 mm long piece of aluminum foil was wrappedaround the joint to increase the cross-section to 5.5 mm so it would fitinto the welder. An induction welder was used to join the ends of thetube together and join them onto the plug. The plug was placed into thedie, clamped, and subjected to a 25 second cycle at 45% power followedby an 8 second soak and a 10 second cooling cycle. After curingovernight, the IVRs were placed in 20 mL of DDI water at 37° C. After 2days, the IVRs had increased in mass by 2-2.3 grams and the inside(lumen) was filled with liquid, which was a mixture of 97 wt % water/3wt % glycerol. Increasing/decreasing the amount of glycerol added to theinterior or increasing/decreasing the amount of water the device isimmersed in will influence the final ratio of glycerol to water, as wellas osmolality of the final solution. The device also could be placed ina mixture such as water and glycerol to soak. This will load water andglycerol into the device. Alternatively, the device is placed into waterfor an initial soaking and then placed in glycerol or another mixture todraw glycerol into the device, as well.

Appropriate agents also may be used to create an osmotic gradient toload the IVRs with aqueous fluid lubricant using agents including, butnot limited to, glycerol, polyethylene glycol, propylene glycol,carrageenan (i.e., sulfated polysaccharides), other lubricating orhydrating substances, salts, and osmotic aqueous agents, etc.

Example 35 DDI Water Reservoir Device

A reservoir IVR filled with DDI water was constructed as follows.Devices filled with a hypo-osmotic solution (e.g., water with little orno additives) were constructed and demonstrated controlled delivery ofwater. In the embodiment described below, the hyper-osmotic vaginalfluid solution in the vaginal cavity osmotically attracts the water orwater vapor from the IVR in a manner that delivers the water from theIVR slowly over a period of time (i.e., several days (1-5 days) andpotentially up to 30 days). The IVRs were constructed using tubing madefrom TECOPHILIC HP-93A-100 with a cross-section of 4.8 mm and a wallthickness of ˜250 μm cut to a length of 120 mm. The same polymer as asolid rod of 4.6 mm cross-section was cut into 20 mm long segments to beused as plugs to seal the tube. Inserting one end of the plug 10 mm intothe tube, a compression spring (120 mm long, 4.01 mm cross-sectionalwidth, 0.51 mm OD wire, 3 coils/cm) was inserted into the tube and theother end of the plug was inserted into the opened end of the tubing toform a closed tube. (In another example, the spring/support was omittedfrom the device.) An induction welder was used to join the ends of thetube together and fuse them onto the plug. The plug with tubing over itwas placed into the die, clamped, and subjected to a 25 second cycle at45% power followed by an 8 second soak and a 10 second cooling cycle.After curing overnight, a 27 gauge needle was inserted along the innerannulus of the IVR through the joint and into the lumen. Another needlewas inserted into the lumen on the other side of the joint. In anotherembodiment the syringe needles were inserted through the inside wall ofthe torus under compression. A 3 mL syringe was used to injectapproximately 1.5 grams of double distilled (DDI) water into the IVRuntil the water started to come out of the other needle, filling the IVRwith liquid. The IVRs were placed in 100 mL of DDI water with theneedles left in place, allowing the polymer to reach equilibriumswelling.

Example 36 Multi-Lumen: Matrix/Reservoir

An IVD was constructed as follows using two different types ofliquid/lubricant reservoirs: a solid and a hollow, or matrix andreservoir, respectively, each holding a different type ofliquid/lubricant. TECOPHILIC HP-93A-100 tubing (cross-sectional diameterof 4.8 mm and wall thickness of 250 μm) was cut to 40.5 mm. TECOPHILICHP-93A-100 polymer rod (cross-section 4.6 mm) was cut to 91.5 mm. Therod section was annealed at 70° C. for 5 minutes inside of a 50 mLbeaker, then air cooled at room temperature to give a circular finalproduct. A stainless steel spring (4.01 mm cross-section, 0.51 mm wirediameter, 3 coils/cm) was cut to 38.45 mm. A 5 mm section of theTECOPHILIC HP-93A-100 tubing was overlapped onto the TECOPHILICHP-93A-100 rod and then wrapped in a 3 mm wide×80 mm long piece ofaluminum foil to increase the cross-section to 5.5 mm. The resultantjoint was induction welded using a split-die welder (HPS-20; PlasticWeldSystems, Inc.) at 45% power for 25 seconds followed by an 8 second soakand a 10 second cool to join the tubing to the rod. The spring wasinserted into the open end of the tube and compressed to allow the otherend of the tube to overlap onto the other end of the TECOPHILICHP-93A-100 rod and then wrapped in a 3 mm wide×80 mm long piece ofaluminum foil to increase the cross-section to 5.5 mm. The resultantjoint was induction welded using a split-die welder (HPS-20; PlasticWeldSystems, Inc.) at 45% power for 25 seconds followed by an 8 second soakand a 10 second cool to join the tubing to the rod, forming a completering. A 27 gauge needle was inserted through each joint into the lumenof the tubing section and a 3 mL syringe was used to fill the lumen withglycerol through one needle while air escaped from the other needle. Inone embodiment TECOFLEX 1-MP Adhesive (Lubrizol Advanced Materials,Inc., Cleveland, Ohio) was then used to seal the needle holes afterfilling.

Example 37 TECOFLEXEG-85A Reservoir Device with Holes/Pores

A reservoir IVR was constructed out of a hydrophobic polymer with poresallowing the release of loaded lubricant/liquid. TECOFLEX EG-85A tubing(5.5 mm cross-section×1.5 mm wall) was cut to 159 mm and the ends weresealed using a bonding die (HPS-EM; preheat 10 seconds, heat 11 seconds,cool 15 seconds, power 16%, travel distance of 3 mm). After sealing theends, a 0.5 mm drill bit was used to drill holes along one side of thesealed tube, approximately every 3 mm starting and ending 20 mm fromeach end to give 40 holes in the rod segment. The holes were onlydrilled into one wall of the tube, forming a channel from the innerlumen to the surface of the tube. After drilling the holes, the endswere welded together using an induction welder (25 seconds of 37% power,12 second soak, 15 second cool) in a configuration placing the drilledholes along the inner annulus of the IVR. A 27 gauge needle and 3 mLsyringe was used to inject the lumen of the TECOFLEX EG-85A side with0.1 grams of a 0.2 wt % methylene blue/K-Y® Brand Jelly mixture. Anidentical device has been fabricated with a removable adhesive strip toprevent leaking of the contents in the device prior to use.

Example 38 Dual Reservoir IVR Device with Polymer Plugs Separating theReservoir Chambers

An IVR containing two separate reservoirs was constructed from ahydrophilic elastomer with a hydrophobic polymer separating the tworeservoirs. These separate reservoirs can be used to hold and releasedifferent liquids/lubricants. In this embodiment, the device wasfabricated from two 80 mm length of hydrophilic aliphatic thermoplasticpolyurethane tubing segment (5.5 mm cross-section×0.7 mm wallthickness). The ends of the hydrophilic aliphatic thermoplasticpolyurethane segment were sealed using a bonding die (HPS-EM). Byplacing the clamp 9 mm from the die opening, a 6 second preheat cyclewas followed by a 7 second heat cycle with a 10 second cooling cyclefollowing. Two 5 mm long segments (5.5 mm cross-section) of TECOFLEXEG-85A were cut to act as separators/connectors. These connectors havethe property of not allowing the aqueous solution lubricant from thefirst segment into the second segment forming two independent volumes. AFenner Drives (Mannheim, Pa.) polyurethane butt welding kit was usedwith maximum power to melt the TECOFLEX EG-85A segments on the ends ofthe tubing segments. These ends were then melted together using the sameprocedure to produce an IVR. A 27 gauge needle was inserted along theinner annulus of the IVR through the joint and into one lumen. Anotherneedle was inserted into the lumen on the other side of the joint and a3 mL syringe was used to inject 0.8 grams of water into the IVR untilthe liquid started to emerge out of the other needle. The same procedurewas repeated with the other chamber except 0.8 g of a 70/30 wt %glycerol/water mixture was used. In one embodiment TECOFLEX 1-MPadhesive was used to seal the syringe needle holes after filling.

Example 39 Tampon-Shaped Reservoir Device

The present example demonstrates an alternative design for a lubricatingdevice. In this embodiment, TECOPHILIC HP-93A-100 tubing (10.1 mmcross-section×1.56 mm wall thickness) was cut to 60 mm. Approximately 2mm of each end of the tube were lightly clamped between two aluminumplates at 145° C. for 20 seconds to seal each end of the tube. A 27gauge needle was inserted on either end of the tube and a syringe wasused to inject glycerol into the tube through one of the needles. In oneembodiment, 1-2 cm of each end of the tube was then dipped intoapproximately 50 mg of TECOFLEX 1-MP adhesive to seal the needle holes.An “unglued” length of 3 cm remained.

Example 40 Dual Reservoir Tampon Device

The present example demonstrates an alternative design for a lubricatingdevice with two different reservoirs delivering different lubricants.Two 30 mm segments of TECOPHILIC HP-93A-100 tubing (9.53 mmcross-section with 1.4 mm wall thickness) were cut. A TECOFLEX EG-85Aplug (7 mm cross-section, 5 mm long) was inserted into the end of eachtube and a Fenner Drives polyurethane butt welding kit was used withmaximum power to melt the plugs into the end of each tube, sealing thetube. After sealing each tube, one end was joined to another end usingthe same procedure to produce an approximately 60 mm long dual reservoirdevice. A 27 gauge needle was inserted through the joint and into onelumen of the device. Another needle was inserted into end of the deviceand a 3 mL syringe was used to inject 0.8 grams of water into the IVRuntil the liquid emerged out of the other needle, thus filling one ofthe chambers. The same procedure was repeated with the other chamberexcept 0.8 g of a 70/30 wt % glycerol/water mixture was used. In oneembodiment TECOFLEX 1-MP adhesive was used to seal the syringe needleholes after filling. One could make a tampon-shaped device with anycombination of solid or hollow sections/lumens similar to themulti-lumen IVR devices that have been prepared.

Example 41 100 wt % Water-Swellable Polyurethane Device

Water swellable polyurethane HP-93A-100 was extrusion molded on a HaakeMinilab (Thermo Electron Corporation, Newington, N.H.) extruder into acord that was 5.5 mm in cross sectional diameter and about 155 mm long.The device was welded using induction welding into a ring shape andannealed on a glass cone for 30 minutes at 70″C. The resultant devicewas measured and swelled in 300 mL vaginal fluid simulant (90.6 mMsodium chloride, 25.6 mM sodium lactate and 17.7 mM acetic acid). Overtwo days the device swelled to its equilibrium mass that wasapproximately two times its initial mass. When placed in the air thedevice would provide moisture to surfaces it was in contact with andwould feel moist to the touch, as well as lose mass in the form ofmoisture to the ambient atmosphere.

Example 42 Matrix and Reservoir Tampon Device

The present example demonstrates an alternative design for a lubricatingdevice with a reservoir section and a matrix section deliveringlubricants. A segment of TECOPHILIC HP-93A-100 tubing (cross-sectionaldiameter of 4.8 mm and wall thickness of 250 μm) was cut to 30 mm.TECOPHILIC HP-93A-100 polymer rod (cross-section 4.6 mm) was cut to 30mm. The TECOPHILIC HP-93A-100 rod section was inserted 10 mm into theend of the tubing section and then wrapped in a 3 mm wide×80 mm longpiece of aluminum foil to increase the cross-section to 5.5 mm. Theresultant joint was induction welded using a split-die welder (HPS-20Y)at 45% power for 25 seconds followed by an 8 second soak and a 10 secondcool to join the tubing to the rod. A 5 mm long section of TECOPHILICHP-93A-100 rod was inserted into the other, open end of the tubingsection and then wrapped in a 3 mm wide×80 mm long piece of aluminumfoil to increase the cross-section to 5.5 mm. The resultant joint wasinduction welded using a split-die welder (HPS-20; PlasticWeld Systems,Inc., Newfane, N.Y.) at 45% power for 25 seconds followed by an 8 secondsoak and a 10 second cool to join the tubing onto the 5 mm rod section,sealing the tubing section. A 27 gauge needle was inserted through thejoint and into the lumen of tubing section. Another needle was insertedinto end of the device and a 3 mL syringe was used to inject 0.2 gramsof water into the IVR until the liquid emerged out of the other needle,thus filling the lumen. In one embodiment TECOFLEX 1-MP adhesive wasused to seal the syringe needle holes after filling. After the TECOFLEX1-MP adhesive had cured for 10 minutes, the device was submerged in 50mL of water to soak/swell the rod/matrix section of the device. Aftersoaking for 24 hours, the rod/matrix section had swollen with 0.45 g ofwater.

Biological Examples Example 43 Procedures for In Vivo Sheep Studies

In vivo efficacy studies using a sheep animal model were performed usingselected IVRs designed to demonstrate delivery of fluid or lubricants inan animal model. The purpose of these studies was to measure the amountof fluid found in the sheep vaginal lumen released from or in responseto various selected IVR designs. The designs described above used in thesheep model include iso-osmolar, hypo-osmolar, and hyper-osmolarsolution containing IVRs such as: 1) iso-osmolar acetate buffer matrixIVR (Example 16.3), 2) 97/3 wt % water/glycerol reservoir IVR (Example34), 3) 70/30 wt % acetate buffer/glycerol matrix IVR (Example 16.5), 4)100% glycerol reservoir IVR (Example 25), 5) 70/30 wt % glycerol/waterreservoir IVR (Example 28), 6) DDI water reservoir IVR (Example 35), 7)DDI water matrix IVR (Example 16.4), 8) naïve/baseline data (no IVR,naïve control), and 9) aliphatic thermoplastic polyurethane (PU) IVR(placebo control IVR). Naïve/baseline data and placebo IVR data wereobtained using N=6 animals for up to 5 consecutive days for each animal.Each IVR design (N=3) was pre-weighed and placed approximately 6-9 cminto the sheep vaginal canal (placed consistently in the vaginal canalnear the cervix). Each IVR design remained in the sheep vagina up to a 5day period.

Example 44 Weck-Cel® Procedure to Determine Vaginal Fluid Amount

To determine the amount of fluid released from or generated as a resultof the IVR design, for each sample, a spear-tipped Weck-Cel® (MedtronicInc., Fridley, Minn.) swab attached to a custom made gel applicatorapparatus was placed onto the vaginal epithelial mucosa at approximately6 cm into the vagina for 2 minutes and held parallel to the floor toensure contact with the vaginal epithelia mucosa. The spear-tippedWeck-Cel® swab readily absorbs up to approximately 400 μl of water oraqueous fluid. The Weck-Cel® swab measurements were made at 6 hours andup to 1, 2, 3, 4, and 5 days. Weck-Cels® swabs were weighed prior to andimmediately following each sample time point to determine the amount offluid collected, as a result of the fluid released or generated in thevaginal canal. The collected Weck-Cel® swab weights were compared tomulti-day naïve/baseline and placebo IVR data for each group of sheep.For statistical assessment, Student's two-tailed t-test with unequalvariance and sample size was used to test the statistical significanceof the change in Weck-Cel® swab weight (α=0.05) in comparison to theplacebo Weck-Cel® swab change in swab weight measurements. The resultsare shown in Table 1. The hypo-osmotic IVR designs show a daily increasein Weck-Cel® fluid collection of approximately 70% to 220% of placebomeasurements. Importantly, for the two hyper-osmotic IVR designs, 100%glycerol reservoir IVRs (Example 25) and 70/30 wt % glycerol/waterreservoir IVRs (Example 28), the Weck-Cel® swab results show astatistically significant (α=0.05, Student's two-tailed t-test) increasein daily vaginal fluid levels over the placebo control measurements forthe up to 5 day test period. The hyper-osmolar solution containing IVRs(both 100% glycerol reservoir IVRs and 70/30 wt % glycerol/waterreservoir IVRs) showed a daily increase of approximately 360 to 470% ofplacebo fluid levels collected using the Weck-Cel® method.

TABLE 1 The in vivo Weck-Cel ® swab sheep results. Weck-Cel ® Mass Masschange % of placebo IVR Design (mg) mass (%) Hypo-osmolar IVRs AcetateBuffer Matrix 27 ± 20 118 ± 88 97% Water/3% Glycerin Reservoir 50 ± 17221 ± 74 DDI Water Reservoir 37 ± 10 162 ± 45 DDI Water Matrix 16 ± 6  69 ± 26 Hyper-osmolar IVRs 70% Acetate Buffer/30% Glycerin Matrix 81 ±30  359 ± 131 100% Glycerin Reservoir  81 ± 19*  358 ± 84* 70%Glycerin/30% Water Reservoir 106 ± 26*  471 ± 113* Data are mean ± SEM(*p < 0.05 compared with placebo IVR control data, Student's two-tailedt-test with unequal variance and sample size). The naïve/baseline dataresulted in a mean Weck-Cel ® mass of 11 ± 6 mg. The placebo IVRsresulted in a mean Weck-Cel ® mass of 23 ± 24 mg. Positive valuesindicate an increase in mass of the Weck-Cel ® swab.

Example 45 Post-Study Difference in IVR Weight (Mass) to Determine FluidRelease from IVRs in Sheep

A second method of monitoring the effect of the IVR device involvedweighing the IVRs before and after placing them in the sheep vaginallumen for 5 days. A reduction (negative change) in weight indicatedfluid release from the IVR as shown in Table 2. After the finalmeasurement time point, the IVRs were removed and cleaned with a 70/30 v% isopropyl alcohol/water solution to eliminate any surface substrate(i.e., residual mucous) and weighed to determine the fluid weight changeof the IVR following exposure to the sheep vaginal epithelial mucosa forup to 5 days. The hypo-osmolar devices (97/3 wt % water/glycerolreservoir, DDI water reservoir, DDI water matrix) and the iso-osmolarIVR (Acetate Buffer matrix) delivered between 100 to 900 milligrams(approximately 100 to 900 μl) of fluid over the up to 5 day periodtested, thus indicating effective delivery of fluid. Student'stwo-tailed t-test with unequal variance and sample size (α=0.05) wasused to compare the change in IVR mass to the change in placebo IVRmass. As expected, these hypo-osmolar IVRs produced statisticallysignificant decreases in IVR masses, showing delivery of liquid to thesheep vagina.

TABLE 2 The in vivo sheep IVR mass change results. Change in IVR MassChange in mass % of change in IVR Design (mg) placebo mass (%)Iso-osmolar IVR Acetate Buffer Matrix −109 ± 15*  −240 ± 32* Hypo-osmolar IVRs 97% Water/3% Glycerin Reservoir −416 ± 55*  −916 ±121* DDI Water Reservoir −860 ± 177* −1892 ± 389*  DDI Water Matrix −404± 3*  −888 ± 7*  Hyper-osmolar IVRs 70% Acetate Buffer/30% Glycerin 276± 30* 608 ± 67* Matrix 100% Glycerin Reservoir 955 ± 86* 2103 ± 189* 70%Glycerin/30% Water Reservoir 916 ± 85* 2016 ± 187* Data are mean ± SEM(*p < 0.05 compared with placebo IVR control data, Student's two-tailedt-test with unequal variance and sample size). The placebo IVRs resultedin an mean change in IVR mass from day 0 to day 5 of 46 ± 2 mg. Negativechanges in mass indicate a loss or delivery or release of fluid from theIVR. Positive changes indicate vaginal fluid or water was absorbed intothe IVR from the vaginal cavity.

Example 46 IVR Mechanical Testing: Force to Compression Data

The IVR mechanical properties of the IVRs examined in sheep were testedby measuring the amount of force needed to compress the ring one-tenthof its initial outer diameter using a cyclical compression-relaxationprogram on an Instron 3342 (Norwood, Mass.) with Bluehill Lite (Norwood,Mass.) software. The ring was placed in a small slotted base and heldupright by minimal pressure from a probe attached to the upper pressuretransducer. The IVRs were compressed 10% of their outer diameter at arate of 1 mm/sec. The force (N) at that compression was measured. Theresults of the force testing before and after insertion in sheep can beseen in Table 3. All IVRs exhibited a force at 10% compression rangebetween 0.4 N and 2.6 N.

TABLE 3 The force at 10% (of outer diameter) compression. Force at 10%Force at 10% compression compression before, after, IVR Type mean ± SD(N) mean ± SD (N) Placebo (aliphatic thermoplastic PEU) 1.03 ± 0.08 0.71± 0.04 Iso-osmolar Acetate Buffer Matrix 1.08 ± 0.02 1.03 ± 0.03 DDIwater matrix 1.30 ± 0.13 1.28 ± 0.09 70/30 wt % Acetate Buffer/Glycerol1.16 ± 0.04 1.21 ± 0.07 100% Glycerol Reservoir 2.55 ± 0.44 1.99 ± 0.4470/30 wt % Glycerol/Water Reservoir 0.44 ± 0.04 0.62 ± 0.06

Example 47 Measuring Glycerol on Weck-Cel® Swabs

Selected Weck-Cel® swabs (6 hours, 3 days, 5 days) from the sheepstudies involving two IVRs containing glycerol (hydrophilic aliphaticthermoplastic polyurethane 70/30 wt % glycerol/DDI water reservoir IVRand the TECOPHILIC HP-60D-35 100 wt % reservoir IVR describedpreviously) were analyzed for glycerol content using the HPLC method ofExample 53.1. The swabs were submerged in 20 mL of phosphate bufferedsaline (PBS, 25 mM and pH 7.4) for 1 week. The amount of glycerolpresent on each swab can be observed in Table 4. The results show thepresence of glycerol, which was released from the devices in the sheepvaginal tract during the 5 day study. The amount of glycerol present oneach swab ranged from approximately 40 to 10,000 μg.

TABLE 4 Amount of Glycerol on Weck-Cel ® swabs. Time Amount glycerol IVRType (hrs) (μg) 70/30 wt % glycerol/water 6 10705 reservoir 72 49 120129 100 wt % glycerol reservoir 6 44 72 46 120 116

Example 48 Measuring Glycerol Content in IVRs

The glycerol content of the 70/30 wt % glycerol/water reservoir IVR and100 wt % glycerol reservoir IVR were measured by extracting the contentsof the IVR after the sheep study and the inner fluid was analyzed forglycerol using the HPLC method of Example 53.1. The amount of glycerolwas found to be 0.175 wt % and 0.144 wt %, respectively, indicating over99% glycerol release from the IVRs.

Example 49 In Vitro Release of H₂O or MeOH into D₂O Release Media

The purpose of these studies was to examine the release characteristicsof various embodiments into a known volume D₂O and to show the movementof liquid across the device membrane. IVRs (hydrophilic siliconepolyurethane matrix (Example 17), TECOPHILIC SP-80A-150 matrix (Example16.2), TECOPHILIC HP-93A-100 reservoir, and hydrophilic aliphaticthermoplastic polyurethane reservoir (Example 32) with a 1.5 mm wallthickness) were immersed in DDI water for 3 days to fill (27 gaugeneedles were used to fill the lumen of the reservoir devices prior toimmersion) and then placed in 30 mL of D₂O. The IVRs were submerged andheld in the solution with 7 gram stainless steel washers. All sampleswere maintained at room temperature without stirring. Samples wereobtained at 1, 3, 6, and 24 hours. The release study was stopped after24 hours, because the samples achieved an equilibrium level of release.The volume collected at each time point was 600 μL. After samplecollection, 600 μL of D₂O was added back to the release media to returnthe volume to 30 mL and the calculation of the amount release wasadjusted for this dilution. A 10 μL volume of acetone was added to eachsample as an internal standard. The samples were analyzed by measuringthe water released from the IVRs into the surrounding release mediausing proton NMR techniques with a DMX 400 MHz NMR Spectrometer (BrukerCorporation, Billerica, Mass.). ¹H NMR (D₂O, δ/ppm): 2.06 (acetone) and4.65 (water). The acetone peak was set to a constant value as aninternal standard. Using this aqueous testing method, the results showequilibrium release was achieved between 6 and 24 hours. This shows thatprotons can diffuse across these membranes in an aqueous environment.The results are shown below in Table 5.

TABLE 5 % Cumulative H₂O release into D₂O. hydrophilic hydrophilicaliphatic silicone thermoplastic polyurethane TECOPHILIC TECOPHILICpolyurethane Time matrix SP-80A-150 HP-60D-100 reservoir, (hr) (%)matrix (%) reservoir (%) 1.5 mm wall (%) 1 64 67 72 47 3 72 72 72 60 682 77 73 71 24 101 73 72 76

It is challenging to measure the release of water using D₂O, because ofthe proton exchange from one oxygen in water to the next. Therefore, weused the lowest molecular weight surrogate for water (methanol) todemonstrate diffusion across the membrane of a low molecular weightmolecule. IVRs (hydrophilic silicone polyether urethane matrix (Example17), TECOPHILIC SP-80A-150 matrix (Example 16.2), hydrophilic aliphaticthermoplastic polyurethane reservoir with a 0.7 mm wall thickness(Example 31), and hydrophilic aliphatic thermoplastic polyurethanereservoir with a 1.5 mm wall thickness (Example 32)) were immersed in a70/30 v % DDI water/methanol mixture for 24 hours to fill (27 gaugeneedles were used to fill the lumen of the reservoir devices prior toimmersion) and then placed in 30 mL of D₂O. The IVRs were submerged andheld in the solution with 7 gram stainless steel washers to make surethe devices were completely immersed. All samples were maintained atroom temperature without stirring. Samples were obtained at 1, 3, and 6hours and 1, 2, 3, 4, and 5 days. The volume collected at each timepoint was 600 μL. After sample collection, 600 μL of D₂O was added backto the release media to bring the volume back to 30 mL and this dilutionwas compensated for in the release calculation known to those skilled inthe art. A 10 μL volume of acetone was added to each NMR sample as aninternal standard for integration and determination of the concentrationof the released methanol. The samples were analyzed by measuring themethanol released from the IVR into the surrounding release media usingproton NMR with a DMX 400 MHz NMR Spectrometer (Bruker Corporation,Billerica, Mass.). ¹H NMR (D₂O, δ/ppm): 2.06 (acetone) and 3.15(methanol). The acetone peak was set to a constant value as an internalstandard. The results show that by changing the wall thickness of thedevice, release of the low molecular weight model for water can bemodulated. The results are shown below in Table 6.

TABLE 6 % Cumulative MeOH release into D₂O. hydrophilic hydrophilicaliphatic aliphatic thermoplastic hydrophilic TECOPHILIC thermoplasticpolyurethane silicone SP-80A- polyurethane reservoir, Time polyurethane150 matrix reservoir, 1.5 mm wall (hr) matrix (%) (%) 0.7 mm wall (%)(%) 1 15 63 61 76 3 16 86 86 101 6 20 94 105 120 24 21 92 108 123 48 2192 103 121 72 22 89 103 120 96 21 87 103 119

Example 50 K-Y® Brand Jelly Lubricant Release Study

The purpose of this study was to examine the in vitro release of thelubricant K-Y® Brand Jelly from IVRs having lumens and pores. Methyleneblue was used to quantify the amount of lubricant released. Thefollowing IVRs were studied: the dual reservoir IVR (Example 38),TECOFLEX IVR reservoir with pores (Example 37), and TECOFLEX IVRreservoir with pores compressed to an outer diameter of 45.2 mm (Example37). All IVRs were filled with a 0.22 wt % mixture of methylene blue inK-Y® Brand Jelly as has been described and then placed in 50 mL of DDIwater at 37° C. and a stir speed of 80 rpm. Samples were obtained at 6hours and 1, 2, 3, 4, and 5 days. Sample size was 1.5 mL and 1.5 mL ofDDI water was immediately replaced to maintain a constant release mediavolume. Samples were analyzed in a Synergy 2 (BioTek, Inc., Winooski,Vt.) plate reader for absorbance at a wavelength of 662 nm.

The results of the K-Y® Brand Jelly in vitro release study can be seenin Table 7. The amount of K-Y® Brand Jelly released was found bymultiplying the amount in milligrams of released methylene blue by 465,because the initially loaded mixture of K-Y® Brand Jelly was 0.22 wt %methylene blue. The results show the ability to release K-Y® Brand Jellyranging from approximately 7 to 315 mg daily from a reservoir IVRconstructed from a hydrophobic polymer containing pores. To support theclaim in this embodiment, the compressed IVR showed a lower dailyrelease possibly due to the closure of some of the pores fromcompression of the outer diameter while other pores were opened by thatcompression as per the claim.

TABLE 7 K-Y ® Brand Jelly release at each time point from each type ofdevice. Dual Time TECOFLEX reservoir Compressed TECOFLEX Reservoir IVR(hr) IVR (mg) reservoir IVR (mg) (mg) 6 6.7 14 −5.4 24 123 103 61 48 174117 76 72 315 141 49 96 114 167 27 120 −2.7 37 30

Example 51 IVR Mechanical Testing: Force to Compression Data

The IVR mechanical properties of the IVRs used in the release studyabove were tested by measuring the amount of force needed to compressthe ring one-tenth of its initial diameter using a cyclicalcompression-relaxation program on an Instron 3342 (Norwood, Mass.) withBluehill Lite (Norwood, Mass.) software. The ring was placed in a smallslotted base and held upright by minimal pressure from a probe attachedto the upper pressure transducer. The IVRs were compressed 10% of theirouter diameter at a rate of 1 mm/sec. The force (N) at that compressionwas measured. The results of the force testing before and after therelease study can be seen in Table 8. All IVRs exhibited a force at 10%compression range between 0.6 N and 1.1 N.

TABLE 8 The force to compress the IVR 10% of outer diameter. Force at10% Force at 10% compression before compression after IVR Type releasestudy (N) release study (N) TECOFLEX reservoir IVR 0.97 0.84 CompressedTECOFLEX 1.06 0.66 reservoir IVR Dual Reservoir IVR 0.72 0.80

Example 52 Pod Release Studies 1. Lactobacillus Release Studies

The purpose of these studies was to examine the in vitro release ofLactobacillus in various embodiments, including pellets inside pods(Example 20), pellets without pods (Example 21), and pellets containingHPC/Lactobacillus (Example 22). Lactobacillus is a probiotic agent andin this embodiment it would be useful to deliver a probiotic agentintravaginally. A matrix pod holder and a reservoir pod holder describedpreviously (Examples 18 and 19 above) were fitted with a pod containinga 100% Lactobacillus pellet (0.17 g) described above in Example 20. TheIVRs were placed in 25 mL of DDI water at 37° C. and a stir speed of 80rpm. Samples were taken at 6 hours and 1, 2, 3, 4, and 5 days. Samplesize obtained was 5 mL and 5 mL of DDI water was immediately replaced tokeep the release media volume constant. Samples were analyzed forLactobacillus release in a cuvette for UV absorbance at a wavelength of220 nm.

In another embodiment, the study above was repeated but with pelletsmade from 50/50 wt % HPC/Lactobacillus as described above in Example 22to examine the effect of HPC on release rate. A 10 mL volume of DDIwater was used as release media and the sample size obtained was 4 mL.Samples were analyzed for Lactobacillus release using UV absorbance at awavelength of 220 nm.

A matrix pod holder was fitted with a 100% Lactobacillus pellet (Example21), without the pod covering to examine the effect on release rate. Thepellet was attached into the pod holder using the TECOFLEX 1-MP adhesiveglue to cover one side of the pellet. After curing the glue overnight,the IVR was placed in 25 mL of DDI water at 37° C., with a stir speed of80 rpm. Samples were obtained at 6 hours and 1, 2, 3, 4, and 5 days. Thesample size was 5 mL and 5 mL of DDI water was immediately replaced.Samples were analyzed for Lactobacillus release in a cuvette for UVabsorbance at a wavelength of 220 nm.

The results for all of the Lactobacillus in vitro release studies areshown below in Table 9. These results show the ability torelease/deliver Lactobacillus from a variety of different pellet/podcombinations with daily release rates ranging between approximately 0 to68 mg daily.

TABLE 9 Lactobacillus release at each time point from each type ofdevice. pellet, 50/50 wt % no pod, Lactobacillus Lactobacillus 50/50 wt% HPC/Lactobacillus matrix only, pod, only, pod, HPC/Lactobacilluspellet, pod, IVR reservoir matrix IVR pellet, pod, matrix reservoir IVRTime (hr) (mg) IVR (mg) (mg) IVR (mg) (mg) 6 0.0 4.2 1.4 NA NA 24 68 2.21.0 2.6 4.0 48 17 1.3 2.4 3.9 11 72 13 4.2 8.9 2.5 1.4 96 3.5 15 12 2.62.9 120 3.2 17 15 −0.5 0.8

2. IVR Mechanical Testing: Force to Compression Data

The IVR mechanical properties of the IVRs from the Lactobacillus releasestudy above were tested by measuring the amount of force needed tocompress the ring one-tenth of its initial diameter using a cyclicalcompression-relaxation program on an Instron 3342 with Bluehill Litesoftware. The ring was placed in a small slotted base and held uprightby minimal pressure from a probe attached to the upper pressuretransducer. The IVRs were compressed 10% of their outer diameter at arate of 1 mm/sec. The force (N) at that compression was measured. Theresults of the force testing before and after the release study can beseen in Table 10. All IVRs exhibited a force at 10% compression rangebetween 0.2 N and 1.3 N.

TABLE 10 The force at 10% of outer diameter compression. Force at Forceat 10% compression 10% compression before release after release IVR Typestudy (N) study (N) Lactobacillus pod matrix IVR 1.15 1.26 Lactobacilluspod reservoir IVR 0.64 0.20

3. HEC Release Study

The purpose of the following studies was to examine the release of HECin a pod/pellet combination. Rhodamine B Isothiocyanate-Dextran was usedto quantify the HEC release. A matrix pod holder and a reservoir podholder described in Examples 18 and 19 above were fitted with a podcontaining a 99/1 wt % HEC/Rhodamine B Isothiocyanate-Dextran pellet(Example 23). The IVRs were placed in 3 mL of DDI water at 37° C. and astir speed of 80 rpm. Samples were taken at days 1, 2, 3, 4, and 5.Sample size was 1.5 mL and 1.5 mL of DDI water was added back. Sampleswere analyzed in a PerkinElmer LS 55 luminescence spectrometer(PerkinElmer, Inc., Waltham, Mass.) (excitation and emission wavelengthswere 570±5 nm and 590±5 nm respectively). In one embodiment, one of thepods had a clear piece of adhesive tape placed over the orifice tosimulate a possible solution to keep the contents from leaking duringstorage. This tape was removed prior to the release study.

The HEC release at each time point can be seen in Table 11. The resultsshow the ability to release HEC from a pod in daily amounts up to 1.65mg.

TABLE 11 HEC release from each device. Time (hr) Pod matrix IVR (mg) Podreservoir IVR (mg) 24 0.24 0.42 48 0.48 0.78 72 0.53 −0.19 96 −0.21 0.38120 0.85 1.65

4. IVR Mechanical Testing: Force to Compression Data

The mechanical properties of the IVRs from Examples above were tested bymeasuring the amount of force needed to compress the ring one-tenth ofits initial diameter using a cyclical compression-relaxation program onan Instron 3342 with Bluehill Lite software. The ring was placed in asmall slotted base and held upright by minimal pressure from a probeattached to the upper pressure transducer. The IVRs were compressed 10%of their outer diameter at a rate of 1 mm/sec. The force (N) at thatcompression was measured. The results of the force testing before andafter the release study can be seen in Table 12. All IVRs exhibited aforce at 10% compression range between 0.37 N and 1.48 N.

TABLE 12 The force on the IVR at 10% of outer diameter compression.Force at Force at 10% compression 10% compression IVR Type before (N)after (N) HEC pod, matrix IVR 1.27 1.48 HEC pod, reservoir IVR 0.80 0.37

Example 53 Glycerol Release Studies 1. Glycerol Quantification by HPLC

Glycerol was quantified by the method of D. Stadnik, L. Gurba, S.Blazej, B. Tejchman-Malecka, Quantitative Analysis of Glycerol inAqueous Pharmaceutical Preparations by RP-HPLC. 60^(th) AnnualPittsburgh Conference on Analytical Chemistry and Applied Spectroscopy(poster presentation), Pittsburgh, Pa. USA (2009). This method uses theoxidation of glycerol to formaldehyde with periodate and the subsequentreaction of the formaldehyde with acetylacetone in the presence ofammonium acetate to form 3,5-diacetyl-1,4-dihydrolutidine (DADHL), whichis the final product detected by HPLC. To determine the amount ofglycerol released from each sample, the samples were diluted from 1:10to 1:500 depending on the sample type or time point. A volume of 100 μLfrom each diluted sample was transferred to an HPLC vial, and 200 μL of3 mM sodium periodate solution in acetate buffer containing 1 M ammoniumacetate and 0.6 M acetic acid and 500 μL of acetylacetone (1% v/v inIPA, prepared fresh) was added to this vial. The vial was placed at 50°C. in a bench top shaker for 20 min and then analyzed via the followinggradient HPLC method to determine the glycerol concentration in releasemedia samples by utilizing the above reaction. Reacted samples wereinjected onto a Zorbax ODS C18, 4.6 mm×250 mm (5 μm pore size) column(Agilent Technologies, Inc., Santa Clara, Calif.), and a gradient methodwas run (Table 13). The final product DADHL was detected at λ=410 nm,with an average retention time of 3.7 min. Solutions of glycerol in DDIwater with known concentrations (ranging from 0.261 to 66.9 μg/mL) werereacted and injected onto the column at the beginning of each HPLCsequence to create a linear calibration curve relating peak area to theconcentration (mg/mL) of the original glycerol solution with peak areasranging from 6.7 to 322.3. The calibration curve was fitted using linearregression (R²=0.997). A peak was determined to represent DADHL elutionfrom the column if the retention time from sample injections matchedthat of standard injections in the same sequence. An Agilent 1200 HPLCwith diode array detector (Agilent Technologies, Inc., Santa Clara,Calif.) was used.

TABLE 13 A 10-minute HPLC method used for DADHL quantification. Time(min) Flow (mL/min) % Solvent A % Solvent B 0 1 60 40 6 1 65 35 8 1 7030 9 1 60 40 10 1 60 40 Solvent A was 0.1 v % TFA in water and Solvent Bwas 0.1 v % TFA in 90/10 v % acetonitrile/water.

2. Glycerol Release Study

The purpose of the following studies was to examine the in vitroglycerol release from various IVDs of the present technology. Theglycerol release from the following types of IVDs was measured:hydrophilic aliphatic thermoplastic polyurethane (cross-section 5.5mm×wall thicknesses of 0.7 mm or 1.5 mm (Examples 29 or 30)),multi-lumen device (Example 36), tampon-shaped device (Example 40), K-Y®Brand LIQUIBEADS® in pod holder (Example 24). All devices have beendescribed above and were filled with glycerol with the exception of theK-Y® Brand LIQUIBEADS® pod holder device. All devices were placed in 400mL of DDI water at 37° C., with a stir speed of 80 rpm. Samples wereobtained at 6 hours and 1, 2, 3, 4, and 5 days (only K-Y® BrandLIQUIBEADS® device sampling was stopped after 24 hours due to completedissolution of the K-Y® Brand LIQUIBEADS® insert). Sample size was 1 mLand water was not replaced after each collection. The internal lumens ofthe IVRs (excluding the K-Y® Brand LIQUIBEADS® device) also wereanalyzed for glycerol content after day 5.

The results for all glycerol in vitro release studies can be seen inTable 14. Note the release for the K-Y® Brand LIQUIBEADS® device is inmilligrams and not percent loaded glycerol. The results show the abilityto delivery/release glycerol from a variety of devices.

TABLE 14 Cumulative glycerol release from each type of device. 1.5 mmMulti- Tampon- 0.7 mm wall wall K-Y ® Brand Time Lumen shaped thicknessthickness LIQUIBEADS (hr) device (%) device (%) device (%) device (%)device (mg) 6 103 8.2 3 7 272 24 109 51 76 41 263 48 111 83 104 123 NA72 107 84 108 123 NA 96 102 69 110 128 NA 120 106 95 111 132 NA Themulti-lumen-, tampon-shaped, 0.7 mm wall thickness, and 1.5 mm wallthickness devices were loaded with approximately 0.51, 2.7, 2.2, and0.82 g of glycerol, respectively.

3. IVR Mechanical Testing: Force to Compression Data

The mechanical properties of select IVDs in the glycerol release studyfrom above were tested by measuring the amount of force needed tocompress the ring one-tenth of its initial diameter using a cyclicalcompression-relaxation program on an Instron 3342 with Bluehill Litesoftware. The ring was placed in a small slotted base and held uprightby minimal pressure from a probe attached to the upper pressuretransducer. The IVRs were compressed 10% of their outer diameter at arate of 1 mm/sec. The force (N) at that compression was measured. Theresults of the force testing before and after the release study can beseen in Table 15. All IVDs exhibited a force at 10% compression rangingbetween 0.68 N to 1.06 N.

TABLE 15 The force at 10% of outer diameter compression. Force at Forceat 10% compression 10% compression IVR Type before (N) after (N) 0.7 mmwall 0.68 0.70 1.5 mm wall 1.06 0.92 multi-lumen IVR 0.81 0.84

Example 54 Evaporation Study, Temperature Change

The present study demonstrates the controlled in vitro loss/delivery ofwater or water vapor from the IVDs listed below. A TECOPHILIC SP-80A-150IVR (Example 16.2) was immersed in 100 mL DDI water for 3 days tohydrate the polymer. A temperature probe was adhered to the surface ofthe hydrated IVR and to the surface of an identical dry, control IVR. Aseparate temperature probe also was used to monitor the roomtemperature. The IVRs were placed at room temperature on the bench-topand temperature was recorded at 5, 10, 15, and 30 minutes and 1, 3, and28 hours.

The results of this in vitro study can be seen in Table 16. When thesurface of the IVR is in contact with air, the surface cooled by 5.5° C.This surface cooling indicates the enthalpically driven change in statefrom condensed, liquid water to gaseous water, known as evaporation.This shows the delivery of water vapor from the IVR surface.

TABLE 16 Evaporation temperatures monitored. Wet IVR Dry IVR Air/RoomTime (min) (active) (° C.) (control) (° C.) (° C.) 0 19.5 22.6 21.9 517.3 22.4 21.9 10 17.0 22.4 22.0 15 16.6 22.0 22.1 30 16.4 21.9 21.9 6017.0 21.9 22.3 180 19.4 22.1 22.1 1680 23.6 23.3 24.0

Example 55 Evaporation Study, Mass Change

In this embodiment, an evaporation study was performed to determine thefluid release rate in a partially enclosed container to provide an invitro model of the vaginal space and demonstrate the controlled releaseof water or water vapor. A TECOPHILIC SP-80A-150 IVR (dry weight 2.88 g,hydrated weight 5.84 g, 2.97 g water) (Example 16.2), a TECOPHILICHP-93A-100 reservoir IVR (dry weight 0.93 g, hydrated weight 3.70 g,2.77 g water) (Example 35) and a hydrophilic silicone polyurethanematrix (dry weight 2.65 g, hydrated weight 3.27 g, 0.62 g water)(Example 17) were immersed (27 gauge needles were used to fill the innerlumen of the reservoir device prior to immersion) in 100 mL of DDI waterfor 3 days to hydrate the polymer. The IVRs were then placed in a 400 mLglass jar with a ¼ inch hole in the top of the jar. The jars were keptat room temperature and the change in mass was monitored at various timepoints over 10 days (121.5 hours for the hydrophilic siliconepolyurethane matrix device).

TABLE 17 Evaporation mass change study. DDI Water DDI Water HydrophilicTECOPHILIC SP- TECOPHILIC HP- silicone 80A-150 60D-100 Reservoirpolyurethane Matrix IVR IVR matrix IVR Time (hrs) Mass Loss (%) MassLoss (%) Mass Loss (%) 0.5 0.3 0.3 1.5 1.5 0.8 0.9 5.0 3 1.6 1.7 9.3 63.0 3.3 20 25.5 13.6 14.1 47 50 26.5 27.9 75 72 37.5 40.0 86 96 50.654.5 96 121.5 63.6 68.7 101 137 75.7 81.2 NA 168 85.7 87.5 NA 240 98.391.3 NA Average 12.2 11.3 5.0 Rate of mass loss (μL/hr):The results of the in vitro study can be seen in Table 17. By day 10,both TECOPHILIC devices had delivered over 90% of their water at a rateof 12 μL/hr and by 121.5 hours, the hydrophilic silicone polyurethanematrix device had delivered just over 100% of its water at a rate of 5.0μL/hr. The results show an extended delivery of water over several days.

Example 56 IVR Mechanical Testing: Force to Compression Data

The IVR mechanical properties of the TECOPHILIC SP-80A-150 IVR andhydrophilic silicone polyurethane IVR from the evaporation study abovewere tested by measuring the amount of force needed to compress the ringone-tenth of its initial diameter using a cyclicalcompression-relaxation program on an Instron 3342 with Bluehill Litesoftware. The ring was placed in a small slotted base and held uprightby minimal pressure from a probe attached to the upper pressuretransducer. The IVR was compressed 10% of its outer diameter at a rateof 1 mm/sec. The force (N) at that compression was measured. TheTECOPHILIC SP-80A-150 IVR exhibited a force at 10% compression rangingfrom 1.37 N before the study to 1.12 N at the completion of the studyand the hydrophilic silicone polyurethane matrix IVR exhibited a forceat 10% compression ranging from 0.48 N before the study to 0.50 N at thecompletion of the study.

EQUIVALENTS

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and apparatuses within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds compositions or biologicalsystems, which can, of course, vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group or combinationsthereof.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges, which can besubsequently broken down into subranges as discussed above. Finally, aswill be understood by one skilled in the art, a range includes eachindividual member. Thus, for example, a group having 1-3 cells refers togroups having 1, 2, or 3 cells. Similarly, a group having 1-5 cellsrefers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is:
 1. An intravaginal device comprising: a firstsegment comprising: an outer surface and a lumen containing an aqueouslubricant, wherein the first segment comprises a water-swellable,hydrophilic polyether polyurethane and is configured to deliver thecontents of the lumen to the outer surface by diffusion.
 2. Theintravaginal device of claim 1 wherein the aqueous lubricant has a pH ofabout 3 to about
 6. 3. The intravaginal device of claim 1 wherein theaqueous lubricant comprises one or more salts, nonaqueous solvents, C1-8carboxylic acids, glucose, antioxidants, preservatives, surfactants,fragrance, flavoring agents, colors, or sweeteners.
 4. The intravaginaldevice of claim 3 where the aqueous lubricant has a pH from 3 to
 6. 5.The intravaginal device of claim 1 wherein the aqueous lubricantcomprises one or more salts, propylene glycol, glycerol, lactic acid,acetic acid, glucose, BHT, ascorbic acid, sorbital, sorbic acid,parabens, EDTA, sodium benzoate, tocopherol, polysorbate 20, polysorbate60, sorbate salts, saccharine, or aspartamate.
 6. The intravaginaldevice of claim 1 wherein the aqueous lubricant is buffered at an acidicpH to promote the natural acidity of the vagina.
 7. The intravaginaldevice of claim 1 wherein the aqueous lubricant comprises vaginal fluidsimulant, about 5 to about 50 mM lactic acid, an acetic acid buffer at apH of about 3.5 to about 5.0, and optionally about 5 to about 50 mMglucose.
 8. The intravaginal device of claim 1 wherein the aqueouslubricant comprises from 4 wt % to 90 wt % glycerol.
 9. The intravaginaldevice of claim 1 wherein the aqueous lubricant comprises from 60 wt %to 95 wt % glycerol.
 10. The intravaginal device of claim 1 furthercomprising an agent selected from the group consisting of drugs andprobiotics.
 11. The intravaginal device of claim 10 wherein the agent isa probiotic selected from the group consisting of Lactobacillus,vitamins, and minerals.
 12. The intravaginal device of claim 1 furthercomprising one or more additional segments, each of which comprises apolymer, an outer surface and optionally a lumen.
 13. The intravaginaldevice of claim 12 wherein the polymer of the one or more additionalsegments is a hydrophobic elastomer.
 14. The intravaginal device ofclaim 12 wherein the hydrophobic elastomer is silicone, siliconepolyurethane, polyurethane, or ethylene-vinyl acetate copolymer.
 15. Theintravaginal device of claim 1 wherein the device is refillable withaqueous lubricant.
 16. The intravaginal device of claim 1 wherein thedevice is a intravaginal ring.
 17. The intravaginal device of claim 16further comprising a spring configured to support the ring or any partthereof.
 18. The intravaginal device of claim 16 wherein the spring isembedded in the ring and encircles at least one lumen of the ring.
 19. Amethod of lubrication comprising administering an intravaginal device ofclaim 1 to a female in need of vaginal lubrication.
 20. The method ofclaim 19 wherein the device delivers 0.001-1000 mg of aqueous lubricantto the outer surface of the device per day.